1,249 results on '"Topoisomerase-I Inhibitor"'
Search Results
2. Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor–Resistant, EGFR-Mutated Non–Small Cell Lung Cancer
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Dong Wan Kim, Melissa Lynne Johnson, Yang Qiu, Hidetoshi Hayashi, Makoto Nishio, Rong Shi, Conor E. Steuer, Pasi A. Jänne, David W. Sternberg, C. Yu, Marianna Koczywas, Christina S. Baik, Michele Vigliotti, Lihui Zhao, Sang-We Kim, Z. Qi, Wu Chou Su, Kathryn A. Gold, Haruyasu Murakami, Helena A. Yu, and James Chih-Hsin Yang
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Patritumab ,Antibody-drug conjugate ,Lung ,biology ,business.industry ,Topoisomerase-I Inhibitor ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Cancer research ,biology.protein ,Medicine ,Non small cell ,Antibody ,business ,Lung cancer ,EGFR inhibitors - Abstract
Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. Significance: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism. See related commentary by Lim et al., p. 16. This article is highlighted in the In This Issue feature, p. 1
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- 2021
3. A stable biocompatible porous coordination cage promotes in vivo liver tumor inhibition
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Yu Liang, Yu Fang, Yong Cui, and Hong-Cai Zhou
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Drug ,Chemistry ,media_common.quotation_subject ,medicine.medical_treatment ,Immunotherapy ,Topoisomerase-I Inhibitor ,Condensed Matter Physics ,Atomic and Molecular Physics, and Optics ,Cell biology ,Cell nucleus ,medicine.anatomical_structure ,In vivo ,Organelle ,medicine ,General Materials Science ,Electrical and Electronic Engineering ,Nucleus ,Camptothecin ,media_common ,medicine.drug - Abstract
Many emerging strategies in chemo-, gene-, and immunotherapy require the accumulation of reagents in the cell nucleus. However, their delivery into the nucleus is often limited. Nuclear delivery could be enhanced with a rationally designed cargo-delivery scaffold, but this approach has rarely been successfully implemented. Herein, a stable, biocompatible molecular capsule that encapsulates and delivers camptothecin, a DNA topoisomerase I inhibitor, into the nucleus of living cells was reported. Nuclear delivery is facilitated by the ultra-small diameter, zero net charge, and hydrophobicity of the capsule. The encapsulated drug complex displays superior toxicity towards multiple cancer cells over the free drug, the Food and Drug Administration (FDA) approved drugs, as well as conventionally reported drug vectors. Additionally, it inhibits liver cancer tumor growth in a xenograft mouse model. Modification of the properties of such molecular capsules may make it possible to design therapeutic strategies that target specific cell organelles.
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- 2021
4. Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs
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Jinal Patel, Ries J. Langley, Petr Tomek, Bruce C. Baguley, David Barker, Euphemia Leung, Ayesha Zafar, Christopher J. Squire, Michelle van Rensburg, Lisa I. Pilkington, Jennifer A. Hollywood, Ivanhoe K. H. Leung, Nuala A. Helsby, William A. Denny, and Jóhannes Reynisson
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TDP1 ,biology ,Chemistry ,Cas9 ,DNA repair ,Topoisomerase ,Topoisomerase-I Inhibitor ,Topoisomerase I ,PARP1 ,Oncology ,Thieno[2,3-b]pyridines ,medicine ,Cancer research ,biology.protein ,Topotecan ,Camptothecin ,Original Research ,medicine.drug - Abstract
Cancer chemotherapy sensitizers hold the key to maximizing the potential of standard anticancer treatments. We have a long-standing interest in developing and validating inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) as chemosensitizers for topoisomerase I poisons such as topotecan. Herein, by using thieno[2,3-b]pyridines, a class of TDP1 inhibitors, we showed that the inhibition of TDP1 can restore sensitivity to topotecan, results that are supported by TDP1 knockout cell experiments using CRISPR/Cas9. However, we also found that the restored sensitivity towards topoisomerase I inhibitors is likely regulated by multiple complementary DNA repair pathways. Our results showed that one of these pathways is likely modulated by PARP1, although it is also possible that other redundant and partially overlapping pathways may be involved in the DNA repair process. Our work thus raises the prospect of targeting multiple DNA repair pathways to increase the sensitivity to topoisomerase I inhibitors. Supplementary Information The online version contains supplementary material available at 10.1007/s40487-021-00158-0.
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- 2021
5. Design, synthesis, and anticancer activities of 8,9-substituted Luotonin A analogs as novel topoisomerase I inhibitors
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Haiping Li, Xiang Yuanhang, Jun Wang, Laichun Luo, Xiaozhi Peng, and Chunling Hu
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biology ,010405 organic chemistry ,Chemistry ,Topoisomerase ,Organic Chemistry ,Pharmacology toxicology ,Topoisomerase-I Inhibitor ,01 natural sciences ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Design synthesis ,biology.protein ,Bioorganic chemistry ,General Pharmacology, Toxicology and Pharmaceutics ,Cancer cell lines - Abstract
A series of 8,9-substituted Luotonin A analogs were designed, synthesized, and evaluated for antiproliferative activity against four cancer cell lines. The structure–activity relationship study revealed that the in vitro anticancer activity of Luotonin A was significantly improved by the introduction of 8-piperazine group and the 5-deaza modification. Two promising compounds 6a and 7a displayed potent topoisomerase I inhibitory activity. And a rational binding mode of 7a with topoisomerase I–DNA complex was proposed based on the molecular docking study.
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- 2021
6. A patent review of topoisomerase I inhibitors (2016–present)
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Endika Martin-Encinas, Carme Masdeu, Francisco Palacios, Gloria Rubiales, Asier Selas, Concepción Alonso, and María Fuertes
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Antineoplastic Agents ,Topoisomerase-I Inhibitor ,01 natural sciences ,Patents as Topic ,03 medical and health sciences ,0302 clinical medicine ,Drug Development ,Neoplasms ,Drug Discovery ,medicine ,Animals ,Humans ,Pharmacology ,chemistry.chemical_classification ,biology ,Chemistry ,Topoisomerase ,fungi ,food and beverages ,Cancer ,General Medicine ,medicine.disease ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Enzyme ,DNA Topoisomerases, Type I ,Drug Design ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Topoisomerase I Inhibitors - Abstract
Topoisomerases are important targets for therapeutic improvement in the treatment of some diseases, including cancer. Inhibitors and poisons of topoisomerase I can limit the activity of this enzyme in its enzymatic cycle. This fact implies an anticancer effect of these drugs, since most cancer cells are characterized by both a higher activity of topoisomerase I and a higher replication rate compared to non-cancerous cells. Clinically approved inhibitors include camptothecin (CPT) and its derivatives. However, their limitations have encouraged different research groups to prepare new compounds, proof of which are the numerous research works and patents, some of them in the last five years.This review covers patent literature on topoisomerase I inhibitors and their application published between 2016-present.The highest contribution toward patent development has been obtained from academics or small biotechnology companies. The most important fields of innovation include the preparation of prodrugs or inhibitors combined with other agents, as biocompatible polymers or antibodies. A promising development of topoisomerase I inhibitors is expected in the next years, directed to the treatment of diverse diseases, specifically toward different types of cancer and infectious diseases, among others.
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- 2021
7. Concise synthesis and in vitro anticancer activity of benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), topoisomerase I inhibitors based on the marine alkaloid lamellarin
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Shotaro Hirao, Masatomo Iwao, Shijiao Zha, Aya Hashirano, Tsutomu Fukuda, and Fumito Ishibashi
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Stereochemistry ,Antineoplastic Agents ,Chemistry Techniques, Synthetic ,Topoisomerase-I Inhibitor ,010402 general chemistry ,01 natural sciences ,Applied Microbiology and Biotechnology ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,Alkaloids ,Cell Line, Tumor ,Heck reaction ,Humans ,Benzopyrans ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Pyrrole ,Natural product ,010405 organic chemistry ,Chemistry ,Alkaloid ,Organic Chemistry ,General Medicine ,In vitro ,0104 chemical sciences ,Intramolecular force ,Topoisomerase I Inhibitors ,Biotechnology - Abstract
Benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs) are potent anticancer compounds having unique BBPIs ring system designed on the basis of the marine natural product lamellarin D. In this study, we describe an alternative synthesis of a 2-demethoxy series of BBPIs, employing van Leusen pyrrole synthesis and an intramolecular Heck reaction as the key reactions. Cytotoxicity of the derivatives against several cancer and normal cell lines is reported.
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- 2021
8. Berberine-10-hydroxy camptothecine-loaded lipid microsphere for the synergistic treatment of liver cancer by inhibiting topoisomerase and HIF-1α
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Guangxuan Liu and Yingjie Qi
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Carcinoma, Hepatocellular ,Berberine ,Mice, Nude ,Pharmaceutical Science ,RM1-950 ,02 engineering and technology ,Topoisomerase-I Inhibitor ,030226 pharmacology & pharmacy ,Microsphere ,liver cancer ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lipid microsphere ,biology ,Chemistry ,Topoisomerase ,Liver Neoplasms ,synergistic treatment ,General Medicine ,Hypoxia-Inducible Factor 1, alpha Subunit ,bbr ,021001 nanoscience & nanotechnology ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,Microspheres ,Rats ,Drug Liberation ,10-hcpt ,Cancer research ,biology.protein ,Camptothecin ,Therapeutics. Pharmacology ,Topoisomerase I Inhibitors ,0210 nano-technology ,Liver cancer ,Research Article - Abstract
10-HCPT is a topoisomerase I inhibitor effective in the treatment of liver cancer but its use is hampered by its resistance. The expression of hypoxia-inducible factor-1α (HIF-1α) is reportedly upregulated in liver cancer tissues, which is directly linked to the resistance of 10-HCPT. While BBR can significantly decrease the level of HIF-1α according to the literature report. Thus, the aim of this study was to prepare a novel intravenous 10-HCPT-BBR-loaded lipid microsphere (LM) and evaluate their synergistic effect on liver cancer treatment. The optimal preparation mainly included 10.0% oil phase (medium-chain triglyceride:long-chain triglyceride = 1:1), emulsifier (egg lecithin E80 and pluronic F68), antioxidant (0.02% NaHSO3), and pH regulator (0.1 mol/L Hcl). Then, the behaviors of BBR-10-HCPT loaded LM in vitro and in vivo were systematically investigated. In vitro, it showed an obvious sustained-release effect in different release mediums, good physicochemical stability at accelerated and long-term storage conditions, and great anti-proliferative capability toward human liver cancer Hep-3B cells. In vivo, the prepared LM exhibited a longer half-life and higher AUC compared to BBR injection and 10-HCPT injection. More importantly, it was found that The LM was distributed more in the liver, spleen, and tumors, but less in the lungs and heart, especially in the lung. And then, it showed significant inhibition of tumor growth against nude mouse with Hep-3B tumor, and the tumor inhibition rate reached 91.55%. Thus, the data obtained in our study suggested that BBR combined with 10-HCPT can raise curative effect and reduce the toxicity of 10-HCPT.
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- 2021
9. Camptothecin-Induced Replication Stress Affects DNA Replication Profiling by E/L Repli-Seq
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Katsuzumi Okumura, Rino Suzuki, Takuya Hayakawa, Shin-ichiro Takebayashi, and Kazuhiro Kagotani
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DNA Replication ,Replication timing ,Retinal pigment epithelium ,DNA Replication Timing ,Cell ,DNA replication ,Retinal Pigment Epithelium ,Biology ,Topoisomerase-I Inhibitor ,Cell biology ,medicine.anatomical_structure ,Replication Initiation ,Replication (statistics) ,Genetics ,medicine ,Humans ,Camptothecin ,Topoisomerase I Inhibitors ,Molecular Biology ,Genetics (clinical) ,medicine.drug - Abstract
E/L Repli-seq is a powerful tool for detecting cell type-specific replication landscapes in mammalian cells, but its potential to monitor DNA replication under replication stress awaits better understanding. Here, we used E/L Repli-seq to examine the temporal order of DNA replication in human retinal pigment epithelium cells treated with the topoisomerase I inhibitor camptothecin. We found that the replication profiles by E/L Repli-seq exhibit characteristic patterns after replication-stress induction, including the loss of specific initiation zones within individual early replication timing domains. We also observed global disappearance of the replication timing domain structures in the profiles, which can be explained by checkpoint-dependent suppression of replication initiation. Thus, our results demonstrate the effectiveness of E/L Repli-seq at identifying cells with replication-stress-induced altered DNA replication programs.
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- 2021
10. The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer
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Jiachen Xuan, Richard B. Pearson, Ross D. Hannan, Shunfei Yan, Piyush B. Madhamshettiwar, Jian Kang, Karen E. Sheppard, Elaine Sanij, Keefe T. Chan, Kaylene J. Simpson, Carleen Cullinane, Sarah Ellis, Madeleine R. C. Tancock, Katherine M. Hannan, and Natalie Brajanovski
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DNA Replication ,Cancer Research ,DNA repair ,DNA damage ,Genes, BRCA2 ,Mice, SCID ,Poly(ADP-ribose) Polymerase Inhibitors ,Topoisomerase-I Inhibitor ,Poly (ADP-Ribose) Polymerase Inhibitor ,Article ,Mice ,03 medical and health sciences ,Targeted therapies ,0302 clinical medicine ,Mice, Inbred NOD ,RNA Polymerase I ,Ovarian cancer ,Cell Line, Tumor ,Animals ,Humans ,Benzothiazoles ,Naphthyridines ,Homologous Recombination ,Polymerase ,Cell Proliferation ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,biology ,Topoisomerase ,DNA replication ,Drug Synergism ,G1 Phase Cell Cycle Checkpoints ,Cystadenocarcinoma, Serous ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,M Phase Cell Cycle Checkpoints ,Drug Therapy, Combination ,Female ,RNA Interference ,Neoplasm Grading ,Topoisomerase I Inhibitors ,Topotecan ,Homologous recombination ,DNA Damage - Abstract
Background Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC. Methods Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC. Results We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo. Conclusions Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.
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- 2020
11. Phase II study of TP300 in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma.
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Propper, David, Jones, Keith, Anthoney, D. Alan, Mansoor, Wasat, Ford, Daniel, Eatock, Martin, Agarwal, Roshan, Michiyasu Inatani, Tomohisa Saito, Masaichi Abe, and Evans, T. R. Jeffry
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STOMACH cancer treatment , *CAMPTOTHECIN , *MEDICATION safety , *DRUG tolerance , *ADENOCARCINOMA , *THERAPEUTICS - Abstract
Background: TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active in oesophagogastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas. Methods: Eligible patients had metastatic or locally advanced gastric or Siewert Types II or III GOJ inoperable adenocarcinoma. Patients were chemotherapy naïve unless this had been administered in the perioperative setting. TP300 was administered as a 1-h intravenous infusion every 3 weeks (a cycle) for up to 6 cycles at a starting dose of 8 mg/m² with intra-patient escalation to 10 mg/m² from cycle 2 in the absence of dose-limiting toxicity. Tumour responses (RECIST 1.1) were assessed every 6 weeks. Toxicity was recorded by NCI-CTCAE version 3.0. Using a modified two-stage Simon design (Stage I and II), a total of 43 patients were to be included providing there were 3 of 18 patients with objective response in Stage I of the study. Results: In Stage I of the study 20 patients (14 males, 6 females), median age 67 years (range 40 - 82), performance status ECOG 0/1, with GC [14] or GOJ carcinoma [6] were enrolled. Of the 16 evaluable patients, 11 received the planned dose increase to 10 mg/m² at cycle 2, 2 decreased to 6 mg/m², and 3 continued on 8 mg/m². There were no objective responses after 2 cycles of treatment. Twelve patients had stable disease for 1 - 5 months and 4 had progressive disease. Median progression free survival (PFS) was 4.1 months (CI [1.6 - 4.9]), median time to progression (TTP) was 2.9 months (CI [1.4 - 4.2]). Grade 3/4 toxicities (worst grade all cycles) included 7 patients (35 %) with neutropenia, 4 patients (20 %) with anaemia, 2 patients (10 %) with thrombocytopenia, and 3 patients (15 %) with fatigue. This study was terminated at the end of Stage I due to a lack of the required (3/18) responders. Conclusions: This study of TP300 showed good drug tolerability but it failed to demonstrate sufficient efficacy as measured by radiological response. [ABSTRACT FROM AUTHOR]
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- 2016
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12. Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low–Expressing Advanced Breast Cancer: Results From a Phase Ib Study
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Junji Tsurutani, Caleb Lee, Ian E. Krop, Shunji Takahashi, Rashmi Krishna Murthy, Alvaro Moreno-Aspitia, Javad Shahidi, Masahiro Sugihara, Haeseong Park, Yasuaki Sagara, Kenji Tamura, Lin Zhang, Charles H. Redfern, Yoshihiko Fujisaki, Hiroji Iwata, Shanu Modi, and Toshihiko Doi
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Adult ,0301 basic medicine ,Cancer Research ,Antibody-drug conjugate ,Immunoconjugates ,Receptor, ErbB-2 ,Advanced breast ,Breast Neoplasms ,Topoisomerase-I Inhibitor ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Trastuzumab ,medicine ,Humans ,In patient ,Neoplasm Metastasis ,Receptor ,Aged ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Immunohistochemistry ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Camptothecin ,Female ,business ,medicine.drug - Abstract
PURPOSE Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) breast cancer (ClinicalTrials.gov identifier: NCT02564900 ) are reported. PATIENTS AND METHODS Eligible patients had advanced/metastatic HER2-low–expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.
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- 2020
13. Comparative in vitro Studies of the Topoisomerase I Inhibition and Anticancer Activities of Metallated N‐Confused Porphyrins and Metallated Porphyrins
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Usein M. Dzhemilev, Nyancy Halder, Harapriya Rath, Vladimir A. D’yakonov, Ilfir R. Ramazanov, and Lilya U. Dzhemileva
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Metalloporphyrins ,Stereochemistry ,Kinetics ,Antineoplastic Agents ,Apoptosis ,Topoisomerase-I Inhibitor ,01 natural sciences ,Biochemistry ,Jurkat cells ,HeLa ,Cell Line, Tumor ,Drug Discovery ,polycyclic compounds ,Humans ,heterocyclic compounds ,General Pharmacology, Toxicology and Pharmaceutics ,Cell Proliferation ,Pharmacology ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Topoisomerase ,Cell Cycle ,Organic Chemistry ,Cell cycle ,biology.organism_classification ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,DNA Topoisomerases, Type I ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Topoisomerase I Inhibitors ,DNA Damage - Abstract
Using the original approach, a series of metallated N-confused porphyrins and metallated porphyrins have been synthesized and characterized. For all the synthesized porphyrins, in vitro studies of cytotoxic activity against K562, U937, HL-60, Jurkat, A549 and HeLa cancer cell lines, the ability to induce apoptosis and effects on the cell cycle as well as the kinetics of proliferative activity of porphyrins and their respective metallated complexes in real time have been developed. The inhibitory activity of metallated porphyrins against human topoisomerase I and the possible mechanism of inhibition have been carried out by modelling using molecular docking.
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- 2020
14. 3-(Benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives as novel scaffold topoisomerase I inhibitor via DNA intercalation: design, synthesis, and antitumor activities
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Cheng-Xue Pan, Nan-Ying Chen, Gui-Fa Su, Hao-Ran Liao, Dong-Liang Mo, Xiao-Juan Li, Guo-Hai Zhang, Jing-Mei Yuan, and Zi-Yu Gu
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biology ,010405 organic chemistry ,Topoisomerase ,General Chemistry ,Topoisomerase-I Inhibitor ,01 natural sciences ,Catalysis ,In vitro ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Biochemistry ,chemistry ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,4-Aminoquinoline ,Materials Chemistry ,biology.protein ,Cytotoxicity ,DNA - Abstract
Twenty-seven 3-(benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives have been designed and synthesized as topoisomerase I inhibitors. The in vitro anti-proliferation evaluation against four human cancer cell lines (MGC-803, HepG-2, T24, and NCI-H460) and one normal cell line (HL-7702) indicated that most of them exhibited potent cytotoxicity. Among them, 5a was identified as the most promising candidate with a low IC50 value of about 2.20 ± 0.14 and was selected for further exploration. Spectroscopic analyses and agarose-gel electrophoresis assays indicated that 5a could interact with DNA and strongly inhibit topoisomerase I (Topo I). Further screening of the Topo I activity of compounds 5b, 5c, 5e, 5f, 5h, 5i, 5j, 5l, and 5n suggested that some of the compounds might exert quite a different cytotoxicity profile to that of 5a. Molecular modeling studies confirmed that 5a adopts a unique mode to interact with DNA and Topo I. Other molecular mechanistic studies suggested that the treatment of MGC-803 cells with 5a induces S phase arrest, up-regulates the pro-apoptotic protein, down-regulates the anti-apoptotic protein, activates caspase-3, and subsequently induces mitochondrial dysfunction so as to induce cell apoptosis. The in vivo efficiency of 5a was also evaluated on MGC-803 xenograft nude mice and the relative tumor growth inhibition was 42.4% at 12 mg kg−1 without an obvious loss in the body weight.
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- 2020
15. Synthesis of New Cu Complex Based on Natural 5Z,9Z-Eicosadienoic Acid: Effective Topoisomerase I Inhibitor and Cytotoxin against the Cisplatin-Resistant Cell Line
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Lilya U. Dzhemileva, Usein M. Dzhemilev, Vladimir A. D’yakonov, and Leisan K. Dil’mukhametova
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U937 cell ,biology ,Chemistry ,Stereochemistry ,HL60 ,General Chemical Engineering ,Topoisomerase ,General Chemistry ,Topoisomerase-I Inhibitor ,Cell cycle ,Jurkat cells ,chemistry.chemical_compound ,Eicosadienoic Acid ,Cell culture ,biology.protein ,QD1-999 - Abstract
The complex (bipy)2Cu(5,9-eicd) was prepared by the reaction of Cu(OAc)2 with 5Z,9Z-eicosadienoic acid and 2,2′-bipyridine in methanol. The new copper complex showed high antitumor activity in vitro toward A2780cis, A2780, Hek293, K562, HL60, Jurkat, and U937 cell lines and efficiently inhibited human topoisomerase I. Using flow cytofluorometry, (bipy)2Cu(5,9-eicd) was studied for the effect on the cell cycle and apoptosis-inducing activity in tumor cells.
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- 2019
16. The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma
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Siquan Chen, Asif Zubair, Ravi C. Kalathur, M. Madan Babu, Jon P. Connelly, Darcie J. Miller, Kaley Blankenship, Min Pan, Michael A. Dyer, Jake E. Batchelder, Shondra M. Pruett-Miller, Brandt C. Huddle, Matthew J. Posgai, Scott C. Blanchard, William C. Wright, Richard H. Chapple, Samuel W. Brady, Sivaraman Natarajan, Payton Archer, John Easton, Elizabeth Stewart, Paul Geeleher, Jonathan Low, Lucy A. Godley, John D. Schuetz, Taosheng Chen, Manbir Sandhu, Burgess B. Freeman, Yingzhe Wang, and Brittney Gordon
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Indoles ,Morpholines ,Science ,Blotting, Western ,Fluorescent Antibody Technique ,Mice, Nude ,General Physics and Astronomy ,Phases of clinical research ,Molecular Dynamics Simulation ,Topoisomerase-I Inhibitor ,Real-Time Polymerase Chain Reaction ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Neuroblastoma ,Targeted therapies ,In vivo ,Cell Line, Tumor ,Target identification ,medicine ,Animals ,Cytotoxic T cell ,Benzothiazoles ,Naphthyridines ,Adverse effect ,Sulfonamides ,Multidisciplinary ,business.industry ,Drug Synergism ,General Chemistry ,Flow Cytometry ,medicine.disease ,In vitro ,Enzyme Activation ,Leukemia ,DNA Topoisomerases, Type II ,Pyrimidines ,Cancer research ,business - Abstract
Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity—often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children., CX-5461 recently progressed through phase I clinical trial as a first-inhuman inhibitor of RNA-POL I. Here, the authors demonstrate that CX-5461 synergizes with topoisomerase I inhibitors to inhibit neuroblastoma cells and that its primary target in this disease is topoisomerase II beta and not RNA-POL I.
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- 2021
17. Corrigendum: 7-Ethyl-10-Hydroxycamptothecin, A DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth
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Lingling Li, Shujuan Wang, Airong Wang, Mengya Li, and Chong Wang
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growth ,Cell ,Caspase 3 ,RM1-950 ,Topoisomerase-I Inhibitor ,SN-38 ,chemistry.chemical_compound ,medicine ,Pharmacology (medical) ,Pharmacology ,biology ,DNA synthesis ,Chemistry ,Cell growth ,Correction ,leukemic cell ,Brief Research Report ,Cell biology ,inhibitor ,medicine.anatomical_structure ,Histone ,Acetylation ,biology.protein ,BRD4 ,Therapeutics. Pharmacology ,DNA - Abstract
7-Ethyl-10-hydroxycamptothecin (SN-38) is an active metabolite of CPT-11, which can inhibit DNA topoisomerase I, DNA synthesis and cause frequent DNA single-strand breaks. In our study, SN-38 was characterized as a potent and reversible BRD4 inhibitor [IC50 = 660.2 nM against BRD4 (BD1) and IC50 = 547.7 nM against BRD4 (BD2)] in biochemical assay using drug repurposing strategy. Additional cellular assay suggested that SN-38 can bind BRD4 in human leukemic cell K562 and inhibit cell growth with IC50 = 0.2798 μM in a BRD4 dependent manner partially. Additionally, mechanism study indicated that SN-38 can induce the accumulation of BRD4 substrate c-Myc and cleavage of caspase 3. In sum, our findings identified BRD4 as a new target of SN-38 and reveals SN-38 as a modifier of histone acetylation reader for the first time, which may provide a new insight for further optimization of dual target inhibitor.
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- 2021
18. TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation
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Jessie D. Trujillo, Emily R. Miraldi, Jan Bakker, Benjamin R. tenOever, Andre L. Moreira, Helen Ray-Jones, Ivan Marazzi, Simin Zheng, Nan Zhao, Laura Campisi, Michael Schotsaert, Zeyu Zhu, Sven Heinz, Elaine Shum, Christopher Benner, Jessica Sook Yuin Ho, Anna Junxia Zhang, Adolfo García-Sastre, Sreeja Parameswaran, Joseph A. Wayman, Matthew T. Weirauch, Anand D. Jeyasekharan, Yesai Fstkchyan, Igor Morozov, Wen-Chun Liu, Minji Byun, Sumit K. Chanda, Sabarish V. Indran, Natasha N. Gaudreault, Mikhail Spivakov, Honglin Chen, Alba Escalera, Bobo Wing-Yee Mok, Kris M. White, Juergen A. Richt, Mariano Carossino, Valeriya Malysheva, Randy A. Albrecht, Tristan X. Jordan, Teresa Aydillo, Robert Sebra, Betsaida Salom Melo, Andrew Chak-Yiu Lee, Sonia Jangra, Udeni B. R. Balasuriya, David A. Meekins, Ernesto Guccione, Siu Ying Lau, Soner Yildiz, Michiel J. Thiecke, David A. Kaufman, Raveen Rathnasinghe, Honglian Liu, and Intensive Care
- Subjects
THP-1 Cells ,Type I ,Pharmacology ,Medical and Health Sciences ,Transgenic ,Mice ,0302 clinical medicine ,inducible genes ,Chlorocebus aethiops ,Lung ,topoisomerase ,0303 health sciences ,Biological Sciences ,Infectious Diseases ,5.1 Pharmaceuticals ,cytokine storm ,Pneumonia & Influenza ,Development of treatments and therapeutic interventions ,medicine.symptom ,transcription ,medicine.drug ,Genetically modified mouse ,Inflammation ,Biology ,Topoisomerase-I Inhibitor ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Vaccine Related ,03 medical and health sciences ,Pharmacotherapy ,topotecan ,Biodefense ,medicine ,Animals ,Humans ,Vero Cells ,030304 developmental biology ,Mesocricetus ,epigenetics ,SARS-CoV-2 ,Prevention ,Inflammatory and immune system ,Topoisomerase ,COVID-19 ,Pneumonia ,medicine.disease ,COVID-19 Drug Treatment ,Emerging Infectious Diseases ,Good Health and Well Being ,inflammation ,biology.protein ,chromatin ,Topotecan ,Topoisomerase I Inhibitors ,Cytokine storm ,030217 neurology & neurosurgery ,DNA Topoisomerases ,Developmental Biology - Abstract
The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans., Graphical abstract, Inhibition of topoisomerase 1 through the FDA-approved molecule topotecan suppresses SARS-CoV-2-infection-associated lethal inflammation in hamster and mouse models without compromising antiviral immune responses.
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- 2021
19. N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents: Synthesis and biological evaluation
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Yuqing Wang, Yingmei Lu, Xiaohong Fan, Tian Luo, Xiaoling Hu, Yiyue Feng, Xiangyong Hao, Dan Liu, Yuying Wang, Liming Jiang, Honghua Zhang, Junfang Li, Tao Shi, and Zhen Wang
- Subjects
Cell Survival ,Topoisomerase Inhibitors ,medicine.medical_treatment ,Antineoplastic Agents ,Topoisomerase-I Inhibitor ,chemistry.chemical_compound ,Structure-Activity Relationship ,Downregulation and upregulation ,Glioma ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Humans ,Benzamide ,Cell Proliferation ,Pharmacology ,Chemotherapy ,Temozolomide ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,General Medicine ,medicine.disease ,Molecular Docking Simulation ,DNA Topoisomerases, Type II ,chemistry ,DNA Topoisomerases, Type I ,Benzamides ,Cancer research ,COX-2 inhibitor ,Drug Screening Assays, Antitumor ,medicine.drug ,Glioblastoma - Abstract
Glioblastoma is one of the most lethal brain tumors. The crucial chemotherapy is mainly alkylating agents with modest clinical success. Given this desperate need and inspired by the encouraging results of a phase II trial via concomitant Topo I inhibitor plus COX-2 inhibitor, we designed a series of N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents based on structure modification on 1,5-naphthyridine derivatives (Topo I inhibitors). Notably, the target compounds I-1 (33.61 ± 1.15 μM) and I-8 (45.01 ± 2.37 μM) were confirmed to inhibit COX-2, while a previous reported compound (1,5-naphthyridine derivative) resulted nearly inactive towards COX-2 (IC50 > 150 μM). Besides, I-1 and I-8 exhibited higher anti-proliferation, anti-migration, anti-invasion effects than the parent compound 1,5-naphthyridine derivative, suggesting the success of modification based on the parent. Moreover, I-1 obviously repressed tumor growth in the C6 glioma orthotopic model (TGI = 66.7%) and U87MG xenograft model (TGI = 69.4%). Besides, I-1 downregulated PGE2, VEGF, MMP-9, and STAT3 activation, upregulated E-cadherin in the orthotopic model. More importantly, I-1 showed higher safety than temozolomide and different mechanism from temozolomide in the C6 glioma orthotopic model. All the evidence demonstrated that N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents could be promising for the glioma management.
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- 2021
20. Repurposing of ginseng extract as topoisomerase I inhibitor based on the comparative analysis of gene expression patterns
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Ho Sub Lee, Jin Woo Choi, Mi Ran Byun, Cheol Hyun Kim, and Sang Kwan Lee
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0106 biological sciences ,Cell Survival ,Panax ,Plant Science ,Synthetic lethality ,Horticulture ,Topoisomerase-I Inhibitor ,Pharmacology ,complex mixtures ,01 natural sciences ,Biochemistry ,Ginseng ,Gene expression ,Tumor Cells, Cultured ,medicine ,Humans ,Molecular Biology ,Molecular Structure ,biology ,Plant Extracts ,010405 organic chemistry ,Gene Expression Profiling ,Topoisomerase ,Drug Repositioning ,food and beverages ,General Medicine ,HCT116 Cells ,0104 chemical sciences ,DNA Topoisomerases, Type I ,Drug development ,biology.protein ,DNA supercoil ,Topoisomerase I Inhibitors ,Camptothecin ,010606 plant biology & botany ,medicine.drug - Abstract
Repositioning of plant extracts and chemical drugs can accelerate drug development. However, its success rate may depend on what the clue is for the repositioning. Recently, repositioning based on correction of unwarranted gene expression pattern has suggested the possibility of new drug development. Here, we designed a similar method for the repositioning of nutraceutical ginseng (Panax ginseng C.A.Mey.), which is one of the most validated natural therapeutic products for various diseases. We analyzed ginseng-induced gene expression profiles using the connectivity map algorithm, which is a database that connects diseases, chemical drugs, and gene expression. Ginseng was predicted to show the same effects as those of topoisomerase I inhibitors. In a subsequent in vitro assay, ginseng extract unwound coiled or supercoiled DNA, an effect comparable to that of the topoisomerase I inhibitor, camptothecin. Furthermore, ginseng extract induced synthetic lethality with suppression of the Werner syndrome gene. The collected data implicate ginseng as a candidate antitumor agent owing to its topoisomerase I inhibitory activity and further validate the usefulness of differentially expressed gene similarity-based repurposing of other natural products.
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- 2019
21. Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold
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Fumiyasu Okazaki, Kenyu Yoshida, Yuko Natsui, Masatomo Iwao, Fumito Ishibashi, Masahiro Fujimoto, Hideto To, Tsutomu Fukuda, and Yusuke Nanjo
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Male ,Indoles ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Topoisomerase I inhibitors ,Topoisomerase-I Inhibitor ,01 natural sciences ,Biochemistry ,Electrophilic substitution ,chemistry.chemical_compound ,Structure-Activity Relationship ,In vivo ,Coumarins ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Biology ,Cell Proliferation ,Mice, Inbred BALB C ,Scaffold hopping ,biology ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Topoisomerase ,Alkaloid ,Organic Chemistry ,Lamellarin D ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,BBPI ,Drug Design ,Colonic Neoplasms ,biology.protein ,Molecular Medicine ,Cattle ,Drug Screening Assays, Antitumor ,Antitumor activity ,Camptothecin ,DNA ,medicine.drug - Abstract
A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan., Bioorganic & Medicinal Chemistry, 27(2), pp.265-277; 2019
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- 2019
22. Combined pharmacophore-guided 3D-QSAR, molecular docking, and virtual screening on bis-benzimidazoles and ter-benzimidazoles as DNA–topoisomerase I poisons
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Upasana Issar, Rita Kakkar, Richa Arora, and Tripti Kumari
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Quantitative structure–activity relationship ,Virtual screening ,Molecular model ,biology ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Topoisomerase ,Topoisomerase-I Inhibitor ,010402 general chemistry ,Condensed Matter Physics ,01 natural sciences ,0104 chemical sciences ,Mechanism of action ,Docking (molecular) ,medicine ,biology.protein ,Physical and Theoretical Chemistry ,medicine.symptom ,Pharmacophore - Abstract
Certain DNA minor groove binders, especially bis-benzimdazole containing compounds, such as Hoechst 33258 and its derivatives, act as potent topoisomerase I inhibitors. The mechanism of action of these drugs is complex and involves hindering the breakage/reunion reaction of topoisomerase I. In the present work, molecular modeling studies have been performed to develop a pharmacophore and 3D-quantitative structure–activity relationship (QSAR) model based on bis- and ter-benzimidazoles, in an attempt to recognize the features that must be present in a molecule for it to behave as a topoisomerase I inhibitor. A data set comprising thirty bis-benzimidazoles and ter-benzimidazoles, known for their cytotoxicity against the RPMI-8402 lymphoblastoma cell line, has been chosen for this study. A five-point common pharmacophore hypothesis (CPH), with two acceptors, one donor and two aromatic features, has been derived for pharmacophore-based alignment of the molecules. The QSAR model, hence generated, shows a reasonable predictive Q2 value of 0.465. The CPH and contour map analyses display features that render antiproliferative properties to molecules against tumor cell lines, thereby ceasing cell growth. Further, the pharmacophore model has been utilized to develop lead molecules that can provide stability to the DNA–topoisomerase I cleavable complex, in turn inhibiting the activity of the enzyme. Virtual screening, followed by docking of obtained hits into the minor groove of B-DNA, gave three potent drugs, which are already approved drugs. The drug having the best fitness and binding score was further docked into the DNA–topoisomerase I cleavable complex. The present study opens up a new dimension in development of drugs for topoisomerase I inhibition.
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- 2019
23. Design and synthesis of a DNA intercalative half-sandwich organoruthenium(<scp>ii</scp>)–chromone complex: cytotoxicity evaluation and topoisomerase Iα inhibition assay
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Sartaj Tabassum, Imtiyaz Yousuf, Farukh Arjmand, and Musheer Ahmad
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Gel electrophoresis ,biology ,Stereochemistry ,Topoisomerase ,02 engineering and technology ,General Chemistry ,Topoisomerase-I Inhibitor ,010402 general chemistry ,021001 nanoscience & nanotechnology ,biology.organism_classification ,01 natural sciences ,Catalysis ,0104 chemical sciences ,HeLa ,chemistry.chemical_compound ,chemistry ,Chromone ,Materials Chemistry ,biology.protein ,A-DNA ,0210 nano-technology ,Cytotoxicity ,DNA - Abstract
In the present study, we report the molecular design and synthesis of [Ru(η6-p-cymene)-(chromone)Cl] complex (1) as a potential topoisomerase I inhibitor. The structural elucidation of complex 1 was carried out by analytical, spectral and single crystal X-ray crystallographic techniques. Complex 1 crystallized in the monoclinic Pc space group with a Ru(II) ion coordinated to a p-cymene arene unit in a usual “piano-stool” geometry. In vitro binding interaction studies of complex 1 with ct-DNA and HSA were carried out and suggested a strong binding affinity towards DNA via an intercalative mode. DNA photocleavage activity was carried out with a pBR322 plasmid DNA substrate to ascertain the cleaving ability and the mechanistic pathway of the cleavage process. Topoisomerase I inhibition assay of complex 1 was performed via gel electrophoresis which revealed a significant inhibitory effect on the enzyme catalytic activity at a minimum concentration of 20 μM. Molecular docking studies of the complex were carried out with DNA, HSA and topoisomerase I to determine the specific binding preferences at the target site and complement the spectroscopic studies. Cytotoxic studies of complex 1 on a series of five human cancer cell lines, viz. A-498, HepG2, HeLa, MCF-7 and MIA-PA-CA-2, by the SRB assay revealed a moderate but selective activity towards pancreatic and cervical cancer cell lines.
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- 2019
24. Regioselective alkylation reaction of the 2′-deoxyctidine with 9-aminomethyl derivatives of SN38
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Lech Kozerski, Robert Kawęcki, Elżbieta Bednarek, Jerzy Sitkowski, Wojciech Bocian, and Beata Naumczuk
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010405 organic chemistry ,Stereochemistry ,Chemical shift ,Organic Chemistry ,Regioselectivity ,Biological activity ,Topoisomerase-I Inhibitor ,Alkylation ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Cancer cell ,Deoxycytidine ,Spectroscopy ,DNA - Abstract
We present first evidence of a spontaneous alkylation of the 2′-deoxycytidine by potential topoisomerase I inhibitors from camptothecins family. The 7-ethyl-9-(N-morpholino)methyl-10-hydroxycamptothecin and the 7-ethyl-9-(N-pyrrolidinyl)methyl-10-hydoxycamptothecin regioselectively alkylate spontaneously an exo-cyclic nitrogen (N4) of the 2′- deoxycytidine. Product of the reaction has been confirmed using NMR techniques and DFT calculation of the carbon chemical shifts. This is the first evidence of spontaneous alkylation of DNA building block, the 2′-deoxycytidine, by this class of compounds, which are biologically active in vitro against several cancer cells, but tolerate normal cells.
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- 2019
25. Small DNA circles as bacterial topoisomerase I inhibitors
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Bing Zhou, Qiang Wang, Dawei Li, Bei Lv, and Qiang Zhuge
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chemistry.chemical_classification ,Nuclease ,biology ,General Chemical Engineering ,Topoisomerase ,02 engineering and technology ,General Chemistry ,Topoisomerase-I Inhibitor ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,Enzyme ,chemistry ,Biochemistry ,biology.protein ,0210 nano-technology ,Cytotoxicity ,Antibacterial drug ,Inhibitory effect ,DNA - Abstract
Bacterial topoisomerase I is a potential target during the course of antibacterial drug therapy. In our studies, specifically designed small DNA circles with high bending stress were synthesized. It is demonstrated that small DNA circles showed high inhibitory effect on the activity of bacterial topoisomerase I and the single-stranded regions associated with bending deformation in DNA circles are believed to be the crucial factor for trapping the enzymes and decreasing the effective concentration of the topoisomerases in the reaction solution. In addition, the DNA circles showed high thermal stability and excellent nuclease resistance. In consideration of the low cytotoxicity of DNA-based biopharmaceuticals, our results may provide a new idea for the future design and optimization of DNA-based therapeutic agents for antibacterial therapy.
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- 2019
26. Synthesis and Evaluation of Topoisomerase I Inhibitors Possessing the 5,13-Dihydro-6H-benzo[6,7]indolo[3,2-c]quinolin-6-one Scaffold
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Tsutomu Fukuda, Masanari Kimura, Gen Onodera, Fumito Ishibashi, Naoki Yoshioka, Masatomo Iwao, Yuri Matsuo, and Fuyuki Matsuoka
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Pharmacology ,Scaffold ,Stereochemistry ,Chemistry ,Organic Chemistry ,Topoisomerase-I Inhibitor ,Analytical Chemistry - Abstract
Novel topoisomerase I inhibitors possessing the 5,13-dihydro- 6H-benzo[6,7]indolo[3,2-c]quinolin-6-one (BIQ) scaffold were designed and synthesized. This scaffold was constructed using sequential and regioselective functionalization of the pyrrole core through palladium-catalyzed cross-coupling, conventional electrophilic substitution, directed lithiation, and subsequent diphenylphosphoryl azide (DPPA)-mediated lactam ring construction. The obtained BIQs were evaluated for their topoisomerase I inhibitory activities and their antiproliferative activities in the panel of 39 human cancer cell lines established by the Japanese Foundation for Cancer Research (JFCR39)., HETEROCYCLES, 99(2), pp.1032?1052; 2019
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- 2018
27. Molecular docking, DFT and antimicrobial studies of Cu(II) complex as topoisomerase I inhibitor
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Shazia Parveen, Musheer Ahmad, Qian-Fan Zhang, Loïc Toupet, Arif O. Khan, Farukh Arjmand, Aligarh Muslim University, Brown University, Jamia Hamdard, Institut de Physique de Rennes (IPR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
endocrine system ,Staphylococcus aureus ,Stereochemistry ,Antineoplastic Agents ,Topoisomerase-I Inhibitor ,Triclinic crystal system ,010402 general chemistry ,01 natural sciences ,Dna cleavage ,Anti-Infective Agents ,Structural Biology ,Escherichia coli ,Molecular Biology ,[PHYS]Physics [physics] ,DNA cleavage ,Topo-I inhibitor ,antimicrobial activity ,010405 organic chemistry ,Chemistry ,General Medicine ,DNA ,molecular docking ,RNA binding ,Antimicrobial ,0104 chemical sciences ,Molecular Docking Simulation ,Topoisomerase I Inhibitors ,Single crystal ,Copper - Abstract
Herein, we report the synthesis and single crystal X-ray structure of Cu(II)-picolinic acid complex, 1 as a potent topoisomerase I inhibitor. The complex 1 crystallized in the triclinic crystal system with space group P-1. Comparative in vitro binding studies of complex 1 with CT DNA and tRNA were carried out revealing an electrostatic binding mode with higher binding propensity towards tRNA. The intrinsic bonding constant value, Kb was calculated to be 4.36 × 104 and 8.78 × 104 M−1 with CT DNA and tRNA respectively. DNA cleavage activity was carried out with a pBR322 plasmid DNA substrate to ascertain the cleaving ability. Furthermore, Topo-I inhibition assay of complex 1, performed via gel electrophoresis revealed a significant inhibitory effect on the enzyme catalytic activity at a minimum concentration of 15 µM. The DFT studies were carried out to provide better insight in the electronic transitions observed in the absorption spectrum of the complex 1. Molecular docking studies were carried out with DNA, RNA and Topo-I to determine the specific binding preferences at the target site and complement the spectroscopic studies. The antimicrobial potential of complex 1 was screened against E. coli, S. aureus, P. aeruginosa, B. subtilis and C. albicans; and compared with doxycycline, exhibiting an excellent maximum zone of inhibition of 28 mm against E. coli. Communicated by Ramaswamy H. Sarma
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- 2021
28. Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer
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Young Bin Cho, Kamal Pandey, Min Sil Kang, Jin Hur, Nar Bahadur Katuwal, Tae Heon Kim, Mithun Ghosh, Yong Wha Moon, Sa Deok Hong, Hee Jung An, and Nahee Park
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Indoles ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Carcinoma, Ovarian Epithelial ,Camptothecin Analogue ,lcsh:Chemistry ,Mice ,Antineoplastic Combined Chemotherapy Protocols ,Phosphorylation ,lcsh:QH301-705.5 ,Spectroscopy ,Ovarian Neoplasms ,Mice, Inbred BALB C ,Sulfonamides ,Cell Cycle ,Drug Synergism ,General Medicine ,Cell cycle ,Immunohistochemistry ,Computer Science Applications ,G2 Phase Cell Cycle Checkpoints ,Sulfoxides ,Female ,ataxia telangiectasia and Rad3-related inhibitor ,Cell Survival ,DNA repair ,Morpholines ,Mice, Nude ,Antineoplastic Agents ,belotecan ,Topoisomerase-I Inhibitor ,Article ,Catalysis ,Inorganic Chemistry ,chemotherapy-resistant ovarian cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell Proliferation ,business.industry ,Organic Chemistry ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,Pyrimidines ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cell culture ,Checkpoint Kinase 1 ,Ataxia-telangiectasia ,Cancer research ,Camptothecin ,Ovarian cancer ,business - Abstract
Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy resistance in the majority of patients. In the chemotherapy-resistant ovarian cancer preclinical model, we investigated whether AZD6738 (an ataxia telangiectasia and Rad3-related (ATR) inhibitor) could synergize with belotecan (a camptothecin analog and topoisomerase I inhibitor). In vitro, both chemotherapy-resistant and chemotherapy-sensitive ovarian cancer cell lines showed synergistic anti-proliferative activity with a combination treatment of belotecan and AZD6738. The combination also demonstrated synergistic tumor inhibition in mice with a chemotherapy-resistant cell line xenograft. Mechanistically, belotecan, a DNA-damaging agent, increased phospho-ATR (pATR) and phospho-Chk1 (pChk1) in consecutive order, indicating the activation of the DNA repair system. This consequently induced G2/M arrest in the cell cycle analysis. However, when AZD6738 was added to belotecan, pATR and pChk1 induced by belotecan alone were suppressed again. A cell cycle analysis in betotecan showed a sub-G1 increase as well as a G2/M decrease, representing the release of G2/M arrest and the induction of apoptosis. In ascites-derived primary cancer cells from both chemotherapy-sensitive and -resistant ovarian cancer patients, this combination was also synergistic, providing further support for our hypothesis. The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer.
- Published
- 2021
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29. SLFN11 is Widely Expressed in Pediatric Sarcoma and Induces Variable Sensitization to Replicative Stress Caused By DNA-Damaging Agents
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Michele Connelly, Jia Xie, Nathaniel R. Twarog, Natasha Sahr, Jessica Gartrell, Hyekyung P. Cho, Anang A. Shelat, Sara M. Federico, Kaley Blankenship, Marcia Mellado-Largarde, Jiyang Yu, Christopher L. Tinkle, Geoffrey Neale, Elizabeth Stewart, Lauren Hoffmann, Koon-Kiu Yan, Armita Bahrami, Shondra M. Pruett-Miller, April Sykes, Michael R. Clay, and Shaina N. Porter
- Subjects
Adult ,Male ,Cancer Research ,Adolescent ,Mice, Nude ,Sarcoma, Ewing ,Topoisomerase-I Inhibitor ,Biology ,Article ,Mice ,Young Adult ,medicine ,Animals ,Humans ,Child ,Sensitization ,Infant, Newborn ,Infant ,Nuclear Proteins ,Genomics ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Apoptosis ,Cell culture ,Child, Preschool ,PARP inhibitor ,Cancer research ,Biomarker (medicine) ,Female ,Sarcoma ,Schlafen family member 11 ,DNA Damage - Abstract
Pediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA-damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress and has been implicated as a potential biomarker to predict sensitivity to DNA-damaging agents (DDA). SLFN11 expression was quantified in 220 children with solid tumors using IHC. Sensitivity to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN) was assessed in sarcoma cell lines, including SLFN11 knock-out (KO) and overexpression models, and a patient-derived orthotopic xenograft model (PDOX). SLFN11 was expressed in 69% of pediatric sarcoma sampled, including 90% and 100% of Ewing sarcoma and desmoplastic small round-cell tumors, respectively, although the magnitude of expression varied widely. In sarcoma cell lines, protein expression strongly correlated with response to TAL and IRN, with SLFN11 KO resulting in significant loss of sensitivity in vitro and in vivo. Surprisingly, retrospective analysis of children with sarcoma found no association between SLFN11 levels and favorable outcome. Subsequently, high SLFN11 expression was confirmed in a PDOX model derived from a patient with recurrent Ewing sarcoma who failed to respond to treatment with TAL + IRN. Selective inhibition of BCL-xL increased sensitivity to TAL + IRN in SLFN11-positive resistant tumor cells. Although SLFN11 appears to drive sensitivity to replicative stress in pediatric sarcomas, its potential to act as a biomarker may be limited to certain tumor backgrounds or contexts. Impaired apoptotic response may be one mechanism of resistance to DDA-induced replicative stress.
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- 2021
30. Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5Z,9Z)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units
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Vladimir A. D’yakonov, Lilya U. Dzhemileva, Regina A. Tuktarova, Usein M. Dzhemilev, and Svetlana R. Ishmukhametova
- Subjects
Lithocholic acid ,lcsh:Medicine ,lcsh:RS1-441 ,Pharmaceutical Science ,Topoisomerase-I Inhibitor ,01 natural sciences ,Jurkat cells ,Article ,lcsh:Pharmacy and materia medica ,HeLa ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,medicine ,cell signaling ,cross-cyclomagnesiation ,5Z,9Z-dienoic acids ,biology ,010405 organic chemistry ,Topoisomerase ,lcsh:R ,apoptosis ,biology.organism_classification ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,anticancer activity ,chemistry ,lithocholic acid ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Ethylene glycol ,Camptothecin ,medicine.drug - Abstract
For the first time, hybrid molecules were synthesized on the basis of lithocholic and (5Z,9Z)-1,14-tetradeca-5,9-dienedicarboxylic acids, obtained in two stages using the homo-cyclomagnesiation reaction of 2-(hepta-5,6-diene-1-yloxy)tetrahydro-2H-pyran at the key stage. The resulting hybrid molecules containing 5Z,9Z-dienoic acids are of interest as novel synthetic biologically active precursors to create modern drugs for the treatment of human oncological diseases. The synthesized hybrid molecules were found to exhibit extremely high in vitro inhibitory activity against human topoisomerase I, which is 2&ndash, 4 times higher than that of camptothecin, a known topoisomerase I inhibitor. Using flow cytometry and fluorescence microscopy, it was first shown that these new molecules are efficient apoptosis inducers in HeLa, U937, Jurkat, K562, and Hek293 cell cultures. In addition, the results of investigations into the effect of the synthesized acids on mitochondria and studies of possible DNA damage in Jurkat tumor cells are also presented.
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- 2021
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31. Computational Approaches Toward Development of Topoisomerase I Inhibitor: A Clinically Validated Target
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Sourav Pal and Arindam Talukdar
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biology ,Chemistry ,Drug discovery ,Topoisomerase ,Topoisomerase-I Inhibitor ,Small molecule ,Chromatin remodeling ,medicine ,biology.protein ,Cancer research ,DNA supercoil ,Topotecan ,Camptothecin ,medicine.drug - Abstract
The importance of topoisomerase type I (Top1) for DNA replication, repairing process, and cell division has made it a significant target for the cancer therapy as well as antibacterial drug target. Top1 enzyme is responsible for relaxing the topological problems associated with DNA supercoiling arising during replication, transcription, and chromatin remodeling. Top1 is expressed much higher in various tumor cells than the normal cells; hence, it is logical that modulating the Top1 levels in tumor cells through small molecule inhibitors can provide anticancer therapy. In bacteria, it has been found that Top1 can prevent excessive negative supercoiling, which has made Top1 as a novel antibacterial drug target. Among different class of Top1 inhibitors, “poisons” exert their antitumor potential by stabilizing the Top1-DNA covalent cleavage complexes. Camptothecin (CPT), identified as a selective Top1 poison, was further developed into two derivatives clinically marketed as anticancer drug (topotecan and irinotecan), which emphasizes the significance of Top1 as a drug target. However, topotecan and irinotecan are not ideal drug molecules as they possess inherently unstable chemical structure, suffer from rapid cellular efflux, and develop cellular resistance. As a result, there is great interest among the medicinal chemistry community toward the development of “non-CPT” agents with different scaffolds such as indolocarbazoles, indenoisoquinolines, and quinolines as Top1 inhibitors. The publication of Top1 crystal structures along with various ligands has provided detail insight about the active site residues important for Top1 inhibition. At the same time, it provided impetus for efforts toward various approaches toward computer-aided design, discovery, and development of Top1 inhibitors. The book chapter will delve upon the various computational approaches that facilitated drug discovery of Top1 inhibitors.
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- 2021
32. Comet assay measures of DNA damage as biomarkers of irinotecan response in colorectal cancer in vitro and in vivo.
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Wood, Joanna P., Smith, Andrew J. O., Bowman, Karen J., Thomas, Anne L., and Jones, George D. D.
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DNA damage , *COLON cancer , *BIOMARKERS , *IRINOTECAN , *LYMPHOCYTES - Abstract
The use of irinotecan to treat metastatic colorectal cancer ( CRC) is limited by unpredictable response and variable toxicity; however, no reliable clinical biomarkers are available. Here, we report a study to ascertain whether irinotecan-induced DNA damage measures are suitable/superior biomarkers of irinotecan effect. CRC-cell lines ( HCT-116 and HT-29) were treated in vitro with irinotecan and peripheral blood lymphocytes ( PBL) were isolated from patients before and after receiving irinotecan-based chemotherapy. Levels of in vitro-, in vivo-, and ex vivo-induced DNA damage were measured using the Comet assay; correlations between damage levels with in vitro cell survival and follow-up clinical data were investigated. Irinotecan-induced DNA damage was detectable in both CRC cell-lines in vitro, with higher levels of immediate and residual damage noted for the more sensitive HT-29 cells. DNA damage was not detected in vivo, but was measurable in PBLs upon mitogenic stimulation prior to ex vivo SN-38 treatment. Results showed that, following corrections for experimental error, those patients whose PBLs demonstrated higher levels of DNA damage following 10 h of SN-38 exposure ex vivo had significantly longer times to progression than those with lower damage levels (median 291 vs. 173 days, P = 0.014). To conclude, higher levels of irinotecan-induced initial and residual damage correlated with greater cell kill in vitro and a better clinical response. Consequently, DNA damage measures may represent superior biomarkers of irinotecan effect compared to the more often-studied genetic assays for differential drug metabolism. [ABSTRACT FROM AUTHOR]
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- 2015
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33. Interrogation of SLFN11 in pediatric sarcomas uncovers an unexpected biological role and a novel therapeutic approach to overcoming resistance to replicative stress
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Kaley Blankenship, Nancy E. Martinez, Armita Bahrami, Geoffrey Neale, Sara M. Federico, Marcia Mellado-Largarde, Christopher L. Tinkle, Hyekyung Plumley, Michele Connelly, Lauren Hoffmann, Anang A. Shelat, Shondra M. Pruett-Miller, April Sykes, Michael R. Clay, Jessica Gartrell, Koon-Kiu Yan, Jiyang Yu, Shaina N. Porter, Elizabeth Stewart, Nathaniel R. Twarog, Jia Xie, and Natasha Sahr
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business.industry ,Intrinsic apoptosis ,Drug resistance ,Topoisomerase-I Inhibitor ,medicine.disease ,chemistry.chemical_compound ,chemistry ,PARP inhibitor ,Cancer research ,Gene silencing ,Medicine ,Talazoparib ,Sarcoma ,business ,Schlafen family member 11 - Abstract
Pediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress, and SLFN11 gene silencing has been implicated as a common mechanism of drug resistance in tumors in adults. We found SLFN11 to be widely expressed in our cohort of pediatric sarcomas. In sarcoma cell lines, protein expression strongly correlated with response to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN), with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, SLFN11 expression was not associated with favorable outcomes in a retrospective analysis of our patient cohort; instead, the protein was retained and promoted tumor growth and evasion. Furthermore, we show that pediatric sarcomas develop resistance to TAL and IRN through impaired intrinsic apoptosis, and that resistance can be reversed by selective inhibition of BCL-XL.Statement of SignificanceThe role of SLFN11 in pediatric sarcomas has not been thoroughly explored. In contrast to its activity in adult tumors, SLFN11 did not predict favorable outcomes in pediatric patients, was not silenced, and promoted tumor growth. Resistance to replicative stress in SLFN11-expressing sarcomas was reversed by selective inhibition of BCL-XL.
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- 2020
34. Tuning the efficacy of esterase-activatable prodrug nanoparticles for the treatment of colorectal malignancies
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Jiahui Jin, Kangkang Ying, Jianqin Wan, Weidong Han, Tongyu Li, Bing Yang, Yuchen Wang, Hangxiang Wang, Shijiang Fang, Xiaona Chen, Binbin Xie, and Haiyang Xie
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Colorectal cancer ,Biophysics ,Nanoparticle ,Bioengineering ,02 engineering and technology ,Topoisomerase-I Inhibitor ,Irinotecan ,Esterase ,Biomaterials ,03 medical and health sciences ,Drug Delivery Systems ,Drug tolerance ,Cell Line, Tumor ,medicine ,Animals ,Prodrugs ,030304 developmental biology ,0303 health sciences ,business.industry ,Esterases ,Prodrug ,021001 nanoscience & nanotechnology ,medicine.disease ,Mechanics of Materials ,Ceramics and Composites ,Cancer research ,Nanoparticles ,Camptothecin ,0210 nano-technology ,business ,Ligation ,Colorectal Neoplasms ,Intracellular - Abstract
Colorectal cancer (CRC) is one of the most common and lethal human cancers, and the clinical outcomes remain unsatisfactory because of the lack of effective and safe therapeutic regimens. Here, we describe a practical and potent delivery approach for the human topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) against CRC. Injectable SN38-loaded nanoparticles are obtained through covalent ligation of the SN38 agent with oligo-e-caprolactone (oligoCL) to form oligoCL-SN38 conjugates via an esterase-activatable linkage followed by encapsulation of these prodrugs in exogenous polymer matrices. Prodrug nanoparticles with adaptive features are sufficiently stable during blood circulation, while active drugs can be released in response to intracellular esterase. The administration of nanoparticle drugs results in durable tumor recession, and the efficacy is superior to that of the current standard-of-care therapy, CPT-11, in multiple mouse models of CRC, one of which is a chemically induced orthotopic CRC. Elucidation of the mechanism underlying these differing efficacies shows that nanoparticle delivery produces a substantial increase in the intratumoral concentration of the therapeutic agent relative to CPT-11, which contributes to improved antitumor efficacy. Finally, these nanoparticle drugs are potentially less toxic in animals than CPT-11, as evidenced by the low incidence of bloody diarrhea and attenuated colonic damage. Overall, these results demonstrate that precisely engineered therapeutic nanoparticles are capable of enhancing efficacy, addressing the risk of tumor recurrence, and increasing drug tolerance, thus deserving further investigation.
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- 2020
35. The bromodomain and extra-terminal domain inhibitor JQ1 synergistically sensitizes human colorectal cancer cells to topoisomerase I inhibitors through repression of Mre11-mediated DNA repair pathway
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Long He, Bin Zhou, Yuan Li, Zong-Guang Zhou, Xuqin Xie, Zhao-Ying Lv, Ke-Ling Chen, Linping Lei, and Wenjun Hu
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0301 basic medicine ,DNA Repair ,DNA repair ,Cell Survival ,Apoptosis ,Synthetic lethality ,Topoisomerase-I Inhibitor ,BET inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,heterocyclic compounds ,Pharmacology (medical) ,neoplasms ,Pharmacology ,MRE11 Homologue Protein ,biology ,Chemistry ,Topoisomerase ,Azepines ,Triazoles ,030104 developmental biology ,Oncology ,MRN complex ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Topotecan ,Camptothecin ,Topoisomerase I Inhibitors ,Colorectal Neoplasms ,medicine.drug - Abstract
Camptothecin (CPT) and its derivatives, irinotecan and topotecan are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs. Mechanistically, they induce DNA double-strand breaks (DSBs). Although CPT is an effective chemotherapeutic agent used in the management of advanced colorectal cancer, there exist associated side effects. Herein, we aimed to establish novel drug combinations that can effectively aid in managing the CPT-related side effects. Besides, bromodomain and extra-terminal domain (BET) inhibitors have proved as promising drugs that target epigenetic mechanisms in various cancers, they alter DNA repair processes, hence are a potential candidate for CPT synthetic lethality. A novel BET inhibitor JQ1 synergized with CPT, exerted antiproliferative effects. Through cell cycle analyses and apoptosis assays, we revealed that a combination of CPT and JQ1 induces subG1-phase arrest and enhances cell apoptosis. This combination increased the intensity of γ-H2AX staining, a specific marker of DSBs. Moreover, colorectal cancer cells highly expressing Top1 showed greater sensitivity to JQ1, which was lowered through the lentiviral shRNA-mediated knockdown of Top1. JQ1, combined with CPT, impeded the recruitment of the Mre11-mediated MRN complex. Finally, JQ1 enhanced the in vivo sensitivity of tumors to CPT without inducing toxicity. These results demonstrate that a combination of BET inhibitor with Top1 inhibitor is safe and exerts positive chemotherapeutic effects in colorectal cancer.
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- 2020
36. Synthesis of novel hybrid quinolino[4,3-b][1,5]naphthyridines and quinolino[4,3-b][1,5]naphthyridin-6(5H)-one derivatives and biological evaluation as topoisomerase I inhibitors and antiproliferatives
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Cinzia Tesauro, Endika Martin-Encinas, Asier Selas, Concepción Alonso, Gloria Rubiales, Birgitta R. Knudsen, and Francisco Palacios
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Aldimine ,Protein Conformation ,Stereochemistry ,Quinolino[4,3-b][1,5]naphthyridin-6-ones ,Quinolino[4,3-b][1,5]naphthyridines ,Antineoplastic Agents ,Chemistry Techniques, Synthetic ,Topoisomerase-I Inhibitor ,Cleavage (embryo) ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Humans ,Naphthyridines ,Cytotoxicity ,Cell Proliferation ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,Antiproliferative effect ,0303 health sciences ,biology ,010405 organic chemistry ,Chemistry ,Topoisomerase ,Organic Chemistry ,General Medicine ,0104 chemical sciences ,Molecular Docking Simulation ,Topoisomerase I ,Enzyme inhibition ,Enzyme ,DNA Topoisomerases, Type I ,Intramolecular force ,Quinolines ,biology.protein ,Topoisomerase I poison ,Topoisomerase I Inhibitors ,DNA - Abstract
The topoisomerase I enzymatic inhibition of hybrid quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridines and quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-ones was investigated. First, the synthesis of these fused compounds was performed by intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and unsaturated aldehydes affording corresponding hybrid 5-tosylhexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one compounds with good to high general yields. Subsequent dehydrogenation led to the corresponding more unsaturated dihydro (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one derivatives in quantitative yields. The new polycyclic products show excellent-good activity as topoisomerase I (TopI) inhibitors that lead to TopI induced nicking of plasmids. This is consistent with the compounds acting as TopI poisons resulting in the accumulation of trapped cleavage complexes in the DNA. The cytotoxic effect on cell lines A549, SKOV3 and on non-cancerous MRC5 was also screened. Tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one 9 resulted the most cytotoxic compound with IC50 values of 3.25 ± 0.91 μM and 2.08 ± 1.89 μM against the A549 cell line and the SKOV3 cell line, respectively. Also, hexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 8a and dihydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 10a showed good cytotoxicity against these cell lines. None of the compounds presented cytotoxic effects against non-malignant pulmonary fibroblasts (MRC-5).
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- 2020
37. Pharmacokinetics of trastuzumab deruxtecan (T-DXd), a novel anti-HER2 antibody-drug conjugate, in HER2-positive tumour-bearing mice
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Yoshitake Furuta, Katsunobu Hagihara, Hiromi Okamoto, Yusuke Ogitani, Hiroshi Kuga, Masataka Oitate, and Hideyuki Shiozawa
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Drug ,endocrine system ,Biodistribution ,Immunoconjugates ,Health, Toxicology and Mutagenesis ,media_common.quotation_subject ,Topoisomerase-I Inhibitor ,Pharmacology ,Toxicology ,Ado-Trastuzumab Emtansine ,030226 pharmacology & pharmacy ,Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pharmacokinetics ,Trastuzumab ,Cell Line, Tumor ,medicine ,Animals ,skin and connective tissue diseases ,neoplasms ,media_common ,biology ,Chemistry ,General Medicine ,body regions ,030220 oncology & carcinogenesis ,Anti-HER2 Antibody ,biology.protein ,Camptothecin ,Antibody ,Topoisomerase I Inhibitors ,Conjugate ,medicine.drug - Abstract
Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice.Following intravenous (iv) administration of T-DXd, the PK profiles of T-DXd and total Ab (the sum of conjugated and unconjugated Ab) were almost similar, indicating that the linker is stable during circulation. Biodistribution studies using radiolabelled T-DXd demonstrated tumour-specific distribution and long-term retention. DXd was the main catabolite released from T-DXd in tumours, with exposure levels at least five times higher than those in normal tissues and seven times higher than those achieved by non-targeted control ADC. Following iv administration of DXd, it was rapidly cleared from the circulation (T1/2; 1.35 h) and excreted mainly through faeces as its intact form.The PK profiles reveal that T-DXd effectively delivers the expected payload, DXd, to tumours, while minimising payload exposure to the systemic circulation and normal tissues. The released DXd is rapidly cleared from systemic circulation, presumably via the bile with negligible metabolism, and excreted through the faeces. Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice. Following intravenous (iv) administration of T-DXd, the PK profiles of T-DXd and total Ab (the sum of conjugated and unconjugated Ab) were almost similar, indicating that the linker is stable during circulation. Biodistribution studies using radiolabelled T-DXd demonstrated tumour-specific distribution and long-term retention. DXd was the main catabolite released from T-DXd in tumours, with exposure levels at least five times higher than those in normal tissues and seven times higher than those achieved by non-targeted control ADC. Following iv administration of DXd, it was rapidly cleared from the circulation (T1/2; 1.35 h) and excreted mainly through faeces as its intact form. The PK profiles reveal that T-DXd effectively delivers the expected payload, DXd, to tumours, while minimising payload exposure to the systemic circulation and normal tissues. The released DXd is rapidly cleared from systemic circulation, presumably via the bile with negligible metabolism, and excreted through the faeces.
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- 2020
38. Self-delivery nanoparticles of an amphiphilic irinotecan-enediyne conjugate for cancer combination chemotherapy
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Yun Ding, Lili Sun, Aiguo Hu, Jing Li, Bing Duan, Yuan Yuan, Baojun Li, and Shuai Huang
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Biomedical Engineering ,Antineoplastic Agents ,Apoptosis ,02 engineering and technology ,Enhanced permeability and retention effect ,Topoisomerase-I Inhibitor ,010402 general chemistry ,Endocytosis ,Irinotecan ,01 natural sciences ,Drug Delivery Systems ,Amphiphile ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Enediyne ,Humans ,General Materials Science ,Chemistry ,Combination chemotherapy ,General Chemistry ,General Medicine ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,0104 chemical sciences ,Nanoparticles ,Enediynes ,0210 nano-technology ,medicine.drug ,Conjugate ,HeLa Cells - Abstract
An amphiphilic small molecular drug self-delivery system was designed by linking a hydrophilic topoisomerase I inhibitor irinotecan (Ir) with a lipophilic cytotoxic enediyne (EDY) antibiotic through an ester bond. The maleimide-based EDY with a pendant carboxyl group was synthesized in four steps from commercially available reagents. The EDY compound possesses the ability to generate radical intermediates at physiological temperature as demonstrated by electron spin resonance analysis and further causes DNA-cleavage and tumor cell suppression. The self-delivery system prepared by the combination of two anticancer drugs, EDY and Ir, formed nanoparticles’ self-assembly with a size of around 60 nm in aqueous solution, enabling the drugs to accumulate in tumor tissues through the enhanced permeability and retention effect. With high drug loading capacity (100%), the Ir–EDY nanoparticles entered tumor cells through endocytosis and possessed strong synergistic effects, inducing tumor cell death through the cell apoptosis pathway efficiently.
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- 2020
39. Molecular Design, Synthesis and Docking Study of Alkyl and Benzyl Derivatives of Robustic Acid as Topoisomerase I Inhibitors
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Huang Maochun, Yogini Jaiswal, Rui Chen, Jiayong Huang, Leonard L. Williams, Lini Huo, Jing Zhong, Wei Jianhua, Yan Liang, and Xing Xia
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Stereochemistry ,Antineoplastic Agents ,Apoptosis ,Bioengineering ,Topoisomerase-I Inhibitor ,01 natural sciences ,Biochemistry ,HeLa ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Cell growth ,Topoisomerase ,Cell Cycle ,General Chemistry ,General Medicine ,biology.organism_classification ,Isoflavones ,Bioactive compound ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,DNA Topoisomerases, Type I ,chemistry ,Cell culture ,Docking (molecular) ,Drug Design ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Topoisomerase I Inhibitors - Abstract
Robustic acid is reported to be a bioactive compound, isolated from the medicinal plant Dalbergia benthamii Prain. Ten alkyl and benzyl derivatives (2a-2j) of robustic acid were designed and synthesized based on molecular docking approaches. The biological activities of most of the synthesized compounds (such as 2g, 2h, and 2i) were closely consistent with the docking results. In particular, 4-O-phenylpropyl substituted compound 2g displayed potent topoisomerase I inhibitory activity as well as cytotoxicity against SMMC-7721, HepG2, and HeLa cell lines. Further biological testing suggests that compound 2g acted mainly by an arrest of the tumor cells in G1 phase of the cell cycle and suppressed cell proliferation by inducing apoptosis. The findings of this study are encouraging with respect to potential utilization of these compounds as new topoisomerase I inhibitors.
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- 2020
40. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
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Petra ter Brugge, Laetitia Fuhrmann, Fabien Reyal, Rania El-Botty, Thibaut Larcher, Laura Sourd, Sophie Château-Joubert, Agnès Noël, Jean-Luc Servely, Léa Huguet, Ivan Bièche, Pierre Foidart, Jos Jonkers, Philippe La Rosa, Pierre Painsec, Sophie Leboucher, Ludivine Morisset, Fariba Nemati, Georges Lucotte, Elodie Montaudon, Didier Decaudin, Christopher R. Mueller, Florence Coussy, Ahmed Dahmani, Marc-Henri Stern, Marie-France Poupon, Nor Eddine Sounni, Sophie Vacher, Adrien Briaux, Yves Pommier, Anne Vincent Salomon, Elisabetta Marangoni, Cécile Reyes, Tatiana Popova, Translational Research Department,Medical Oncology Department, Genetics Department, Institut Curie, Translational Research Department, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), PSL Research University, UMR3306, Département Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genetics Department, University of Santiago de Compostela, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), U830, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), Université de Liège, Translational Research Department, Medical Oncology Department, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Surgery Department, CRLCC Paul Strauss, U932, Immunity and Cancer, Queen's cancer reserach institute, Queen's University, Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, ProdInra, Archive Ouverte, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade de Santiago de Compostela [Spain] (USC ), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), PSL Research University, U900, and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes
- Subjects
Anthracycline ,DNA repair ,Ubiquitin-Protein Ligases ,[SDV]Life Sciences [q-bio] ,Triple Negative Breast Neoplasms ,Topoisomerase-I Inhibitor ,Irinotecan ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,CHEK1 ,skin and connective tissue diseases ,030304 developmental biology ,0303 health sciences ,biology ,Retinoblastoma ,business.industry ,Topoisomerase ,Nuclear Proteins ,General Medicine ,medicine.disease ,eye diseases ,3. Good health ,[SDV] Life Sciences [q-bio] ,Retinoblastoma Binding Proteins ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Topoisomerase I Inhibitors ,business ,Schlafen family member 11 ,medicine.drug - Abstract
Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.
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- 2020
41. Ectopic Expression of the Meiotic Protein SYCP2 in Breast Cancer Promotes Homologous Recombination and Endows Broad Resistance to DNA Repair-Targeted Drugs
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Haibo Yang, Luyuan Zhang, Li Lan, Jian Ouyang, Siang-Boon Koh, Boya Gao, Shanhoon Lee, Yumin Wang, Leif W. Ellisen, Lee Zou, Xiao-Song Wang, and Xiaolan Zhu
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Cisplatin ,DNA repair ,DNA damage ,Topoisomerase ,RAD51 ,Topoisomerase-I Inhibitor ,Biology ,medicine.disease ,Breast cancer ,Cancer research ,medicine ,biology.protein ,Homologous recombination ,medicine.drug - Abstract
Drugs targeting the DNA damage response (DDR) pathway are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a component of the meiotic synaptonemal complex, is ectopically expressed in breast cancer and associates with broad resistance to DDR-targeted drugs including Cisplatin, inhibitors for PARP, topoisomerase II and topoisomerase I. SYCP2 overexpression correlates with poor prognosis in breast cancer patients and with decreased survival in a clinical trial of antibody-conjugated topoisomerase I inhibitor. SYCP2 overexpression is sufficient to enhance homologous recombination (HR) and confer DDR-targeted drugresistance. Mechanistically, SYCP2 responds to DNA double strand breaks via its lysine/arginine residues and promotes RAD51 localization to DNA breaks by interacting with RAD51. SYCP2 promotes HR independently of BRCA1, suggesting that SYCP2 is a BRCA-independent determinant of DNA damage sensitivity. Thus, SYCP2, which enhances HR, is potentially a biomarker for breast cancer diagnosis, a predictor of DDR-targeted drug response, a prognostic marker for patient outcome, and a target in breast cancer therapy.
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- 2020
42. Novel phosphine sulphide gold(i) complexes: topoisomerase I inhibitors and antiproliferative agents
- Author
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Jesús M. Martínez-Ilarduya, Verónica Conejo-Rodríguez, Birgitta R. Knudsen, Concepción Alonso, Francisco Palacios, Jesús A. Miguel, Endika Martin-Encinas, and Gloria Rubiales
- Subjects
Models, Molecular ,Phosphines ,Antineoplastic Agents ,Sulfides ,Topoisomerase-I Inhibitor ,Complejos de oro ,Crystallography, X-Ray ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,Inorganic Chemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Coordination Complexes ,Cell Line, Tumor ,Humans ,Structure–activity relationship ,Molecule ,Cytotoxicity ,Density Functional Theory ,Cell Proliferation ,A549 cell ,Topoisomerase ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Quinoline ,Topoisomerasa ,0104 chemical sciences ,DNA Topoisomerases, Type I ,chemistry ,A549 Cells ,biology.protein ,Gold ,Drug Screening Assays, Antitumor ,Topoisomerase I Inhibitors ,Gold complexes ,Phosphine - Abstract
Producción Científica, This work describes the synthesis of the gold(I) complexes of phosphine sulphides. The formation of these new derivatives has been confirmed by X-ray crystallography. The coordination of gold(I) with the sulphur atom of the phosphine sulphides favors the inhibition of topoisomerase I as well as a high cytotoxicity of the gold(I)-complexed compounds against the cancer line A549 with IC50 values in the nanomolar range and IC50 values below 5 μM against the SKOV3 cell line. It should be noted that the cytotoxicities observed for the new gold(I) complexes are higher than those observed for phosphine sulphide ligands before binding to gold. Furthermore, the results also indicate that the presence of a nitrogenated heterocycle, such as tetrahydroquinoline or quinoline, is also necessary for the TopI inhibition to be maintained. In addition, no toxicity was observed when the non-cancerous lung fibroblast cell line (MRC5) was treated with the new phosphine sulphide gold(I) complexes prepared., Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación - Fondo Europeo de Desarrollo Regional (grant RTI2018-101818-B-I00), Ministerio de Economía, Industria y Competitividad (grant CTQ2017-89217P), Gobierno Vasco - Universidad del País Vasco (grant IT 992-16)
- Published
- 2020
43. Antibacterial activity of a DNA topoisomerase I inhibitor versus fluoroquinolones in Streptococcus pneumoniae
- Author
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Patricia Mateos-Martínez, María Teresa Antonio García, Adela G. de la Campa, Mirian Domenech, Fernando González-Camacho, Myriam V. Valenzuela, and Ministerio de Economía y Competitividad (España)
- Subjects
0301 basic medicine ,Moxifloxacin ,Levofloxacin ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Microbiología ,Biochemistry ,DNA gyrase ,Antibiotics ,Medicine and Health Sciences ,Enzyme Inhibitors ,Multidisciplinary ,biology ,Antimicrobials ,Pharmaceutics ,Chemistry ,Drugs ,Pneumococcus ,Antimicrobial ,Bacterial Pathogens ,Anti-Bacterial Agents ,Streptococcus pneumoniae ,Medical Microbiology ,DNA Gyrase ,Medicine ,Pathogens ,Research Article ,Fluoroquinolones ,medicine.drug ,DNA Topoisomerase IV ,Topoisomerase IV ,Science ,030106 microbiology ,Topoisomerase-I Inhibitor ,Research and Analysis Methods ,Microbiology ,03 medical and health sciences ,Drug Therapy ,Microbial Control ,medicine ,Benzodioxoles ,Molecular Biology Techniques ,Microbial Pathogens ,Molecular Biology ,Pharmacology ,Bacteria ,Topoisomerase ,Organisms ,Biology and Life Sciences ,Streptococcus ,Bacteriology ,Phenanthrenes ,biochemical phenomena, metabolism, and nutrition ,Genética ,030104 developmental biology ,Biofilms ,Antibiotic Resistance ,Enzymology ,biology.protein ,Antimicrobial Resistance ,Topoisomerase I Inhibitors ,Bacterial Biofilms ,Cloning - Abstract
The DNA topoisomerase complement of Streptococcus pneumoniae is constituted by two type II enzymes (topoisomerase IV and gyrase), and a single type I enzyme (topoisomerase I). These enzymes maintain the DNA topology, which is essential for replication and transcription. While fluoroquinolones target the type II enzymes, seconeolitsine, a new antimicrobial agent, targets topoisomerase I. We compared for the first time the in vitro effect of inhibition of topoisomerase I by seconeolitsine and of the type II topoisomerases by the fluoroquinolones levofloxacin and moxifloxacin. We used three isogenic non-encapsulated strains and five non-vaccine serotypes isolates belonging to two circulating pneumococcal clones, ST638 (2 strains) and ST1569V (3 strains). Each group contained strains with diverse susceptibility to fluoroquinolones. Minimal inhibitory concentrations, killing curves and postantibiotic effects were determined. Seconeolitsine demonstrated the fastest and highest bactericidal activity against planktonic bacteria and biofilms. When fluoroquinolone-susceptible planktonic bacteria were considered, seconeolitsine induced postantibiotic effects (1.00-1.87 h) similar than levofloxacin (1.00-2.22 h), but longer than moxifloxacin (0.39-1.71 h). The same effect was observed in sessile bacteria forming biofilms. Seconeolitsine induced postantibiotic effects (0.84-2.31 h) that were similar to those of levofloxacin (0.99-3.32 h) but longer than those of moxifloxacin (0.89-1.91 h). The greatest effect was observed in the viability and adherence of bacteria in the postantibiotic phase. Seconeolitsine greatly reduced the thickness of the biofilms formed in comparison with fluoroquinolones: 2.91 ± 0.43 μm (seconeolitsine), 7.18 ± 0.58 μm (levofloxacin), 17.08 ± 1.02 μm (moxifloxacin). When fluoroquinolone-resistant bacteria were considered, postantibiotic effects induced by levofloxacin and moxifloxacin, but not by seconeolitsine, were shorter, decreasing up to 5-fold (levofloxacin) or 2-fold (moxifloxacin) in planktonic cells, and up to 1.7 (levofloxacin) or 1.4-fold (moxifloxacin) during biofilm formation. Therefore, topoisomerase I inhibitors could be an alternative for the treatment of pneumococcal diseases, including those caused by fluoroquinolone-resistant isolates. This study was supported by grant BIO2017-82951-R from Plan Nacional de I+D+I of the Ministry of Economy and Competitiveness (to AGC). Sí
- Published
- 2020
44. Synthesis of DNA interactive C3-trans-cinnamide linked β-carboline conjugates as potential cytotoxic and DNA topoisomerase I inhibitors
- Author
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Shalini Nekkanti, Nagula Shankaraiah, Manda Sathish, Yellaiah Tangella, Narayana Nagesh, Ahmed Kamal, Soujanya Thatikonda, Namballa Hari Krishna, Sabanis Chetan Dushantrao, Shirisha Cherukommu, G. Srinivas, and Ramya Tokala
- Subjects
0301 basic medicine ,Cell Survival ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Topoisomerase-I Inhibitor ,Biochemistry ,HeLa ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Cytotoxic T cell ,Molecular Biology ,biology ,DNA synthesis ,Viscosity ,Circular Dichroism ,Topoisomerase ,Cell Cycle ,Organic Chemistry ,DNA ,biology.organism_classification ,Amides ,Intercalating Agents ,Molecular Docking Simulation ,Spectrometry, Fluorescence ,030104 developmental biology ,chemistry ,Cinnamates ,Cell culture ,Docking (molecular) ,030220 oncology & carcinogenesis ,NIH 3T3 Cells ,biology.protein ,Molecular Medicine ,Spectrophotometry, Ultraviolet ,Topoisomerase I Inhibitors ,Carbolines - Abstract
A series of new C3-trans-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13–45 nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.
- Published
- 2018
45. Benzoxazines as new human topoisomerase I inhibitors and potential poisons
- Author
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Ismail Yalcin, Esin Aki-Yalcin, Betul Tekiner-Gulbas, Cigdem Ozen, Nuran Diril, Ilkay Yildiz, Egemen Foto, and Fatma Zilifdar
- Subjects
Intercalation (chemistry) ,Poison control ,Topoisomerase-I Inhibitor ,01 natural sciences ,Catalysis ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Medicine ,IC50 ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,DNA ligase ,biology ,010405 organic chemistry ,business.industry ,Topoisomerase ,Building and Construction ,DNA ,0104 chemical sciences ,Benzoxazines ,chemistry ,Biochemistry ,DNA Topoisomerases, Type I ,biology.protein ,Topoisomerase I Inhibitors ,business ,Camptothecin ,Methyl group ,medicine.drug ,Research Article - Abstract
BACKGROUND: The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. OBJECTIVES: In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. METHODS: We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. RESULTS: While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC(50):8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC(50):0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC(50):0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R(2) position were play a role for increasing of its poisonous effect. CONCLUSION: As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. [Figure: see text]
- Published
- 2019
46. Molecular docking study and structure-based design of novel camptothecin analogues used as topoisomerase I inhibitor
- Author
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Adamu Uzairu and David Ebuka Arthur
- Subjects
0301 basic medicine ,biology ,Chemistry ,Stereochemistry ,Topoisomerase ,Intercalation (chemistry) ,General Chemistry ,Topoisomerase-I Inhibitor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Docking (molecular) ,030220 oncology & carcinogenesis ,biology.protein ,medicine ,Structure based ,Inhibition constant ,Camptothecin ,medicine.drug - Published
- 2018
47. Histone deposition promotes recombination-dependent replication at arrested forks
- Author
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Sarah Lambert, Dingli Dai, Karine Fréon, Brigitte Hartmann, Fatemeh Mojallali, Ana Teixeira-Silva, Françoise Ochsenbein, Julien Hardy, Louise Dupoiron, Anissia Ait Saada, Stress génotoxiques et cancer, Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE11-0028,REPLICAF,Structure et mechanisme de l'assemblage de la chromatine associée à la réplication(2016), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), and Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
- Subjects
Genome instability ,Cancer Research ,Gene Expression ,Yeast and Fungal Models ,Cell Cycle Proteins ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,QH426-470 ,Biochemistry ,Histones ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics (clinical) ,Recombination, Genetic ,0303 health sciences ,biology ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Chromosome Biology ,Eukaryota ,Chromatin ,Cell biology ,Nucleosomes ,Nucleic acids ,Histone ,Experimental Organism Systems ,Schizosaccharomyces pombe ,Epigenetics ,Research Article ,Saccharomyces cerevisiae Proteins ,DNA repair ,Nucleic acid synthesis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Saccharomyces cerevisiae ,Topoisomerase-I Inhibitor ,DNA replication ,Genomic Instability ,03 medical and health sciences ,Saccharomyces ,Model Organisms ,Ribonucleases ,DNA-binding proteins ,Schizosaccharomyces ,Genetics ,Nucleosome ,Chemical synthesis ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Biology and life sciences ,DNA synthesis ,Organisms ,Fungi ,DNA Helicases ,Proteins ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Cell Biology ,DNA ,Chromatin Assembly and Disassembly ,Yeast ,Rad52 DNA Repair and Recombination Protein ,Research and analysis methods ,Biosynthetic techniques ,chemistry ,Mutation ,biology.protein ,Animal Studies ,Schizosaccharomyces pombe Proteins ,Protein Multimerization ,030217 neurology & neurosurgery ,Molecular Chaperones - Abstract
Replication stress poses a serious threat to genome stability. Recombination-Dependent-Replication (RDR) promotes DNA synthesis resumption from arrested forks. Despite the identification of chromatin restoration pathways after DNA repair, crosstalk coupling RDR and chromatin assembly is largely unexplored. The fission yeast Chromatin Assembly Factor-1, CAF-1, is known to promote RDR. Here, we addressed the contribution of histone deposition to RDR. We expressed a mutated histone, H3-H113D, to genetically alter replication-dependent chromatin assembly by destabilizing (H3-H4)2 tetramer. We established that DNA synthesis-dependent histone deposition, by CAF-1 and Asf1, promotes RDR by preventing Rqh1-mediated disassembly of joint-molecules. The recombination factor Rad52 promotes CAF-1 binding to sites of recombination-dependent DNA synthesis, indicating that histone deposition occurs downstream Rad52. Histone deposition and Rqh1 activity act synergistically to promote cell resistance to camptothecin, a topoisomerase I inhibitor that induces replication stress. Moreover, histone deposition favors non conservative recombination events occurring spontaneously in the absence of Rqh1, indicating that the stabilization of joint-molecules by histone deposition also occurs independently of Rqh1 activity. These results indicate that histone deposition plays an active role in promoting RDR, a benefit counterbalanced by stabilizing at-risk joint-molecules for genome stability., Author summary DNA replication occurs in the context of DNA packaged into chromatin. At replication fork, the parental chromatin is evicted and re-assembled, together with newly synthetized histones, onto newly replicated DNA thanks to a network of histone chaperones. The progression of replication forks is often interrupted by a plethora of fork obstacles that affect replisome functionality. Such dysfunctional forks are fragile structures prone to chromosomal rearrangements and chromatin changes, leading to human diseases including cancer. Homologous recombination plays a crucial role in the recovery of dysfunctional forks. We have genetically altered the process of histone deposition-coupled to DNA synthesis to interrogate the contribution of chromatin assembly during fork recovery by homologous recombination. We found that histone deposition acts during fork recovery in a manner that recombination structures are protected from disassembly by helicases such as Rqh1. Histone deposition-coupled to fork recovery favors deletion-type recombinant. Chromatin assembly during fork recovery requires only a subset of the histone chaperones normally acting at canonical forks, namely CAF-1 and Asf1. CAF-1 associates to sites of recombination-dependent DNA synthesis during fork recovery. We propose that restarted forks remain coupled to histone deposition, a benefit counterbalanced by the risk to stabilize recombination intermediates detrimental to genome stability.
- Published
- 2019
48. Polymer conjugated graphene-oxide nanoparticles impair nuclear DNA and Topoisomerase I in cancer
- Author
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Aditi Nandi, Sudipta Basu, and Chandramouli Ghosh
- Subjects
Cisplatin ,biology ,Chemistry ,Topoisomerase ,General Engineering ,Bioengineering ,General Chemistry ,Topoisomerase-I Inhibitor ,Endocytosis ,biology.organism_classification ,Small molecule ,Atomic and Molecular Physics, and Optics ,HeLa ,chemistry.chemical_compound ,Cancer cell ,biology.protein ,Biophysics ,medicine ,General Materials Science ,DNA ,medicine.drug - Abstract
Cancer chemotherapy had been dominated by the use of small molecule DNA damaging drugs. Eventually, the emergence of DNA damage repair machinery in cancer cells has led to combination therapy with the DNA topology controlling enzyme, topoisomerase I inhibitor along with DNA impairing agents. However, integrating multiple drugs having diverse water solubility and hence bio-distribution effectively for cancer treatment remains a significant challenge, which can be addressed by using suitable nano-scale materials. Herein, we have chemically conjugated graphene oxide (GO) with biocompatible and hydrophilic polymers [polyethylene glycol (PEG) and ethylene-diamine modified poly-isobutylene-maleic anhydride (PMA-ED)], which can encompass highly hydrophobic topoisomerase I inhibitor, SN38. Interestingly, these sheet structured GO-polymer-SN38 composites self-assembled into spherical nanoparticles in water after complexing with a hydrophilic DNA damaging drug, cisplatin. These nanoparticles showed much improved colloidal stability in water compared to their drug-loaded non-polymeric counterpart. These SN38 and cisplatin laden GO-polymer nanoparticles were taken up by HeLa cancer cells through clathrin-dependent endocytosis to home into lysosomes within 6 h, as confirmed by confocal microscopy. A combination of gel electrophoresis, flow cytometry, and fluorescence microscopy showed that these nanoparticles damaged nuclear DNA and induced topoisomerase I inhibition leading to apoptosis and finally improved HeLa cell death. These self-assembled GO-polymer nanoparticles can be used for strategic impairment of multiple cellular targets involving hydrophobic and hydrophilic drugs for effective combination therapy.
- Published
- 2019
49. Encapsulation and Enhanced Delivery of Topoisomerase I Inhibitors in Functionalized Carbon Nanotubes
- Author
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Kwang Rok Kim, Yong Chae Jung, Kyung-jin Lee, Byumseok Koh, Jeong-O Lee, Young-O Kim, Dahee Kim, Sunjoo Ahn, Dasol Lee, Sieun Chae, and Sang Dal Rhee
- Subjects
chemistry.chemical_classification ,Aqueous medium ,Chemistry ,Cell growth ,General Chemical Engineering ,Carboxylic acid ,02 engineering and technology ,General Chemistry ,Carbon nanotube ,Topoisomerase-I Inhibitor ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Combinatorial chemistry ,Article ,0104 chemical sciences ,law.invention ,lcsh:Chemistry ,lcsh:QD1-999 ,law ,medicine ,0210 nano-technology ,Camptothecin ,medicine.drug - Abstract
The topoisomerase I inhibitors SN-38 and camptothecin (CPT) have shown potent anticancer activity, but water insolubility and metabolic instability limits their clinical application. Utilizing carbon nanotubes as a protective shell for water-insoluble SN-38 and CPT while maintaining compatibility with aqueous media via a carboxylic acid-functionalized surface can thus be a strategy to overcome this limitation. Through hydrophobic-hydrophobic interactions, SN-38 and CPT were successfully encapsulated in carboxylic acid functionalized single-walled carbon nanotubes and dispersed in water. The resulting cell proliferation inhibition and drug distribution profile inside the cells suggest that these drug-encapsulated carbon nanotubes can serve as a promising delivery strategy for water-insoluble anticancer drugs.
- Published
- 2018
50. VIG-1 is required for maintenance of genome stability in Caenorhabditis elegans
- Author
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Nam Jeong Cho, Yang-Seo Park, and Bala Murali Krishna Vasamsetti
- Subjects
0301 basic medicine ,Genome instability ,lcsh:R5-920 ,VIG-1 ,DNA damage ,Mutant ,chromosome segregation ,Endogeny ,Biology ,Topoisomerase-I Inhibitor ,biology.organism_classification ,DNA damage response ,Phenotype ,General Biochemistry, Genetics and Molecular Biology ,Germline ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,lcsh:Biology (General) ,Animal Science and Zoology ,Caenorhabditis elegans ,lcsh:Medicine (General) ,lcsh:QH301-705.5 ,genome stability - Abstract
To explore the function of VIG-1 in Caenorhabditis elegans, we analyzed the phenotypes of two vig-1 deletion mutants: vig-1(tm3383) and vig-1(ok2536). Both vig-1 mutants exhibited phenotypes associated with genome instability, such as a high incidence of males (Him) and increased embryonic lethality. These phenotypes became more evident in succeeding generations, implying that the germline of vig-1 accumulates DNA damage over generations. To examine whether vig-1 causes a defect in the DNA damage response, we treated worms with UV or camptothecin, a specific topoisomerase I inhibitor. We observed that the embryonic survival of the vig-1 mutants was reduced compared with that of the wild-type worms. Our results thus suggest that VIG-1 is required for maintaining genome stability in response to endogenous and exogenous genotoxic stresses.
- Published
- 2018
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