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In silico prediction of cell line cytotoxicity considerably decreases time and financial costs during drug development of new antineoplastic agents. (Q)SAR models for the prediction of drug-like compound cytotoxicity in relation to nine breast cancer cell lines (T47D, ZR-75-1, MX1, Hs-578T, MCF7-DOX, MCF7, Bcap37, MCF7R, BT-20) were created by GUSAR software based on the data from ChEMBL database (v. 30). The separate datasets related with IC50 and IG50 values were used for the creation of (Q)SAR models for each cell line. Based on leave-one-out and 5F CV procedures, 24 reasonable (Q)SAR models were selected for the creation of a freely available web-application (BC CLC-Pred: ) to predict substance cytotoxicity in relation to human breast cancer cell lines. The mean accuracies of prediction r2, RMSE, Balance Accuracy for the selected (Q)SAR models calculated by 5F CV were 0.599, 0.679 and 0.875, respectively. As a result, BC CLC-Pred provides simultaneous quantitative and qualitative predictions of IC50 and IG50 values for most of the nine breast cancer cell lines, which may be helpful in selecting promising compounds and optimizing lead compounds during the development of new antineoplastic agents against breast cancer. [ABSTRACT FROM AUTHOR]

Background: Site-specific transport of medicinal products to malignant cells and tissues is an intriguing area since it has an ability to safeguard healthy cells. Selective upregulation of folate receptors on colon cancer cells is usual. Consequently, folate receptors have become one of extensively studied target moieties for targeting the delivery of chemotherapeutics. Hence, the study aimed to anchor folic acid, chitosan and oxaliplatin to the functionalized nanotube (FA-CHI-FSWCNT-OXA) for targeting folate receptors on colon cancer cells. The purification process of single-walled carbon nanotubes (SWCNTs) involved the use of an ultrasonic-assisted acid digestion method. The developed complex was evaluated using FTIR, DSC, SEM, XRD and in vitro dissolution studies. SRB and MTT assays were used to assess in vitro cytotoxicity of oxaliplatin and FA-CHI-FSWCNT-OXA) against HT29 and COLO320DM cell lines. Further, progression of apoptosis in cells was investigated using flow cytometry. Results: The FTIR results corroborated drug attachment over carbon nanotube (CNT), whereas the TEM results validated the nanosizing (1–300 nm) of the developed system. Drug entrapment in CNT was found to be 93.43 ± 1.65%, and in vitro drug release was found to be 94.73 ± 0.90% after 24 h. The complex reduced viability of 92.35 ± 0.942% cells than oxaliplatin's 66.58 ± 0.38% inhibition, revealed by MTT assay. In the SRB assay, the developed system showed 91.22 ± 0.90% inhibition, whereas oxaliplatin showed 76.69 ± 0.52% inhibition against HT29 cells. Conclusions: Conclusively, the developed system exhibited better cytotoxicity effects as compared with plain oxaliplatin. Our findings are suggestive of the potential development of CNT-anchored antineoplastic agents for target-specific delivery. [ABSTRACT FROM AUTHOR]

Objectives: To assess the anticancer effects of recently developed compounds, Sa, Sb, Sc, and Sd. These compounds were designed to specifically target the carbonic anhydrase enzyme in solid tumors. Methods: The chemical synthesis involved the use of sulfanilamide, chloroacetyl chloride, GABA, thionyl chloride, methanol, hydrazine hydrate, potassium hydroxide, carbon disulfide, and benzyl chloride derivatives. Docking studies were conducted using the MOE software program version 2015.10, and cytotoxic activity was predicted using the MTT assay. Results: The newly synthesized compounds exhibited notable antineoplastic activity in both in silico and cell line investigations. Although they showed a significant difference in potency compared to cisplatin against cancer cells, they also demonstrated significant differences in toxicity towards normal cells. When compared to acetazolamide, compounds Sb displayed an IC50 = 28.41 µM, which was significantly different, and compound Sd showed a non-significant difference with an IC50 = 61.20 µM against MCF7 cells. Additionally, Sb and Sd demonstrated significant difference in toxicity, with IC50 = 279.02 µM and 194.00 µM, respectively, against MCF10a cells. These findings indicate a significant difference compared to acetazolamide for the Sb compound and suggest that the synthesized compounds hold potential for further development as antineoplastic agents. Furthermore, the results from the cell line study align with the in silico study, where both compounds Sb and Sd exhibited higher S scores compared to acetazolamide, implying a stronger binding affinity with the receptor's catalytic site. The presence of a substituted 1, 2, 4-triazole ring in these compounds contributed to enhanced flexibility and improved interaction with the receptor. Conclusion: A new synthesized compounds exhibited cytotoxicity and demonstrated inhibitory potencies against carbonic anhydrase. [ABSTRACT FROM AUTHOR]

Medicinal plants have duly been implicated in the development of typical antineoplastic agents. Here, the medicinal plant under discourse, Trichosanthes dioica Roxb., commonly known as Pointed gourd in English, Potol in Bengali, is a climber vine found wild and cultivated all over the plains of India and its neighbouring countries for its fruits, consumed as a favoured vegetable. The present work attempts to assemble and critically assess the literature outcome of the antineoplastic potential of T. dioica root. The antineoplastic effects involved cytotoxic, antimitotic, antitumor and cancer chemopreventive potential of its root - mediated through multifaceted mechanisms. The cytotoxic, antimitoitic and antioxidant effects together may furnish the mechanistic grounds for its reported antitumor and cancer chemopreventive activities. Further studies on T. dioica root in this direction, may afford newer effective antitumor leads/drugs from this plant part. [ABSTRACT FROM AUTHOR]

Regarding the development of new antineoplastic agents, with a view to assess the selective antitumoral potential which aims at causing irreversible damage to cancer cells while preserving the integrity of their healthy counterparts, it is essential to evaluate the cytotoxic effects in both healthy and malignant human cell lines. In this study, a complex with two Pd(II) centers linked by the biogenic polyamine spermine (Pd2Spm) was tested on healthy (PNT-2) and cancer (LNCaP and PC-3) prostate human cell lines, using cisplatin as a reference. To understand the mechanisms of action of both cisplatin and Pd2Spm at a molecular level, Fourier Transform Infrared (FTIR) and Raman microspectroscopies were used. Principal component analysis was applied to the vibrational data, revealing the major metabolic changes caused by each drug, which were found to rely on DNA, lipids, and proteins, acting as biomarkers of drug impact. The main changes were observed between the B-DNA native conformation and either Z-DNA or A-DNA, with a higher effect on lipids having been detected in the presence of cisplatin as compared to Pd2Spm. In turn, the Pd-agent showed a more significant impact on proteins. [ABSTRACT FROM AUTHOR]

Stevia urticifolia Thunb. is an underexploited herb possessing bioactive flavonoids, saponins, and terpenoids. The aim of this study was to examine the antiproliferative and toxicogenetic properties of the ethyl acetate extract from Stevia urticifolia aerial parts (EtAcSur) upon Artemia salina, erythrocytes, Allium cepa and sarcoma 180 cells and fibroblasts, as well as in vivo studies on mice to determine systemic, macroscopic, and behavioral alterations and bone marrow chromosomal damage. The assessment using A. salina larvae and mouse blood cells revealed LC50 and EC50 values of 68.9 and 113.6 µg/ml, respectively. Root growth and mitosis were inhibited by EtAcSur, and chromosomal aberrations were detected only at 100 μg/ml. EtAcSur exhibited potent concentration-dependent viability reduction of S180 and L-929 cells and antioxidant capacity employing ABTS• and DPPH•. No previous in vivo studies were performed before with the EtAcSur. Signals of acute toxicity were not observed at 300 mg/kg. Physiological and toxicological investigations at 25 and 50 mg/mg/day i.p. for 8 days did not markedly change body or organ relative weights, nor patterns of spontaneous locomotor and exploratory activities. In contrast, clastogenic effects on bone marrow were found at 50 mg/mg/day. EtAcSur was found to (1) produce toxicity in microcrustaceans, (2) capacity as free radical scavenger, (3) antimitotic, cytotoxic and clastogenic activties upon vegetal and mammalian cells, and (4) lethality on both tumor and normal murine cells indistinctly. In vivo damage systemic effects were not remarkable and clinical signals of toxicity were not observed, suggesting the significant pharmacological potential of S. urticifolia for the development of antineoplastic agents. Abbreviations: ABTS: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); DMSO: dimethylsulfoxide; DPPH: 1,1-diphenyl-2-picrylhydrazyl; EC50: effective concentration 50%; EtAcSur: ethyl acetate extract from Stevia urticifolia aerial parts; Hb, hemoglobin; IC50: inhibitory concentration 50%; LC50,: lethal concentration 50%; MI: mitotic index; RBC, red blood cells; Trolox: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. [ABSTRACT FROM AUTHOR]

Heterocyclic nucleus is vital in medicinal chemistry and has allured significant attention in chemotherapeutic domain. Oxadiazole, a five-membered nitrogen–oxygen-containing heterocyclic core has remarkable anticancer activity. Mechanism associated in defeating tumor corresponds with inhibiting various enzymes and growth factors. Considering the importance of oxadiazole and its derivatives in this panic issue worldwide, this review has discussed research carried out from last 7 years and also their future outlook in drug development as antineoplastic agents. The objective of this review is to emphasize on anticancer activity of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives. The precised features and framework of each research topic is introduced for helping the readers in understanding the perspective of the context in better way. [ABSTRACT FROM AUTHOR]

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Drug combination administration had an enhanced cytotoxic effect compared to single drug. • Z-DNA conformation occurred mostly in polynuclear complexes while A-DNA conformation happened more often in cisplatin. • Single drug administration reveals a higher damage to DNA while the combined administration showed a higher impact on proteins. Over the years, osteosarcoma therapy has had a significative improvement with the use of a multidrug regime strategy, increasing the survival rates from less than 20 % to circa 70 %. Different types of development of new antineoplastic agents are critical to achieve irreversible damage to cancer cells, while preserving the integrity of their healthy counterparts. In the present study, complexes with two and three Pd(II) centres linked by the biogenic polyamines: spermine (Pd 2 SpmCl 4) and spermidine (Pd 3 Spd 2 Cl 6) were tested against non-malignant (osteoblasts, HOb) and cancer (osteosarcoma, MG-63) human cell lines. Either alone or in combination according to the EURAMOS-1 protocol, they were used versus cisplatin as a drug reference. By evaluating the cytotoxic effects of both therapeutic approaches (single and drug combination) in HOb and MG–63 cell lines, the selective anti-tumoral potential is assessed. To understand the different treatments at a molecular level, Synchrotron Radiation Fourier Transform Infrared and Raman microspectroscopies were applied. Principal component analysis and hierarchical cluster analysis are applied to the vibrational data, revealing the major metabolic changes caused by each drug, which were found to rely on DNA, lipids, and proteins, acting as biomarkers of drug-to-cell impact. The main changes were observed for the B-DNA native conformation to either Z-DNA (higher in the presence of polynuclear complexes) or A-DNA (preferably after cisplatin exposure). Additionally, a higher effect upon variation in proteins content was detected in drug combination when compared to single drug administration proving the efficacy of the EURAMOS-1 protocol with the new drugs tested. [ABSTRACT FROM AUTHOR]

• We established a TME-responsive polydopamine-coated cobalt boride (CoB@PDA) for chemotherapy, photothermal therapy and photodynamic therapy. • CoB@PDA was confirmed to be an excellent NIR responsive material with photothermal and photodynamic performance under irradiation. • H 2 O 2 could be decomposed by CoB@PDA into O 2 , ·O 2 − and 1O 2. O 2 was converted further to ROS to generate enhanced ROS-based antitumor action. • CoB@PDA reacted with acid, giving H 2 for reducing inflammation caused by hyperthermia of PTT and Co2+ for causing DNA damage and resulting in cell apoptosis. • Under 808 nm laser irradiation, CoB@PDA showed PTT and PDT effects and achieves outstanding killing effect on tumor cells. The co-ordination properties of biomolecules with metal ions can lead to changes in their structures and functions. This work discloses that cobalt ions (Co2+) can induce structural changes in DNA by coordinating with guanine and inactivate copper/zinc superoxide dismutase (Cu/Zn-SOD) by changing the secondary structure. The Co2+ at high concentrations can suppress cell growth and induce apoptosis. Herein, we fabricate a light and tumor microenvironment (TME) dual-responsive polydopamine-coated cobalt boride (CoB@PDA) as a Co2+-carrying material, NIR-driven photothermal/photodynamic agent, catalase-like nano-enzyme, reactive oxygen species (ROS) moderator, and hydrogen (H 2) supplier. CoB@PDA with catalase-like properties can convert the H 2 O 2 at tumor site into O 2 , ·O 2 − and 1O 2 , thus inducing oxidative stress and alleviating tumor hypoxia. Under 808 nm irradiation, CoB@PDA can induce a hyperthermia by photothermal effect and trigger photosensitization of O 2 to toxic 1O 2 , thus achieving the photothermal therapy (PTT) and photodynamic therapy (PDT) actions. Meanwhile, decomposition of CoB@PDA in the acidic TME releases Co2+ to inhibit the growth of residual tumor cells post phototherapy and H 2 to suppress the inflammatory response induced by phototherapy. The complete ablation of solid tumors with no side effects and recurrence indicates that CoB@PDA is promising for cancer therapy, and thus it provides valuable insights for the development of multifunctional antineoplastic agents. [ABSTRACT FROM AUTHOR]

Cassava extracts containing cyanogenic compounds demonstrate anticancer properties. The cyanogenic glucoside linamarin found abundantly in cassava can release hydrogen cyanide (HCN) upon hydrolysis, a potent cytotoxin. However, linamarin's hydrolysis mechanism by human enzymes is poorly delineated and constitutes a bottleneck for therapeutic development. This study aimed to investigate linamarin's hydrolysis mechanism by human β-glucosidase and identify structural derivatives with enhanced hydrolytic potential using density functional theory calculations. Results revealed α-anomeric derivatives as promising, with leaving group ability and steric bulk strongly governing hydrolysability. We identified several linamarin analogs with predicted rapid hydrolysis kinetics that may enable swift cytotoxic HCN release against cancer cells. This investigation enriches understanding of cyanogenic glycoside reactivity to facilitate their development as targeted antineoplastic agents. The identified derivatives set the groundwork for experimental evaluation of enhanced linamarin-inspired compounds as innovative cancer therapeutics. [Display omitted] • Cassava extracts with linamarin, a cyanogenic compound, have shown anticancer effects. • Linamarin, upon hydrolysis, can release hydrogen cyanide (HCN), a strong cytotoxin. Yet, the mechanism of its hydrolysis by human enzymes remains unclear, complicating therapeutic development. • The study's goal was to explore the hydrolysis mechanism of linamarin by human β-glucosidase and to identify structural derivatives with increased hydrolytic potential using density functional theory calculations. • The study found that α-anomeric derivatives are promising candidates. Factors such as the ability of the leaving group and steric bulk significantly affect hydrolysability. [ABSTRACT FROM AUTHOR]

Cancer is a global public health problem characterized by deviations in the mechanisms that control cell proliferation, resulting in mutations and variations in the structure of DNA. The mechanisms of action of chemotherapeutic drugs are related to their interactions and binding with DNA; consequently, the development of antineoplastic agents that target DNA has extensively focused on use of acridine, a heterocyclic molecule that binds to deoxyribonucleic acid via intercalation, a process that modifies DNA and makes replication impossible. In this context, this study aimed to computationally investigate how acridine intercalators interact with DNA by evaluating the mechanism of interactions, binding, and interaction energies using quantum mechanics calculations. Molecular electrostatic potential (MEP) analysis revealed that acridine has well- distributed negative charges in the center of the molecule, indicative of a dominant electron-rich region. Acridine exhibits well-defined π orbitals (HOMO and LUMO) on the aromatic rings, suggesting that charge transfer occurs within the molecule and may be responsible for the pharmacological activity of the compound. Structural analysis revealed that acridine interacts with DNA mainly through hydrogen bonds between H Acridine ... O DNA with bond lengths ranging from 2.370 Å to 3.472 Å. The Binding energy (ΔE Bind) showed that acridine interacts with DNA effectively for all complexes and the electronic energy results (E+ZPE) for complexes revealed that the complexes are more stable when the DNA-centered acridine molecule. The Laplacian-analysis topological QTAIM parameter (∇2ρ(r)) and total energy (H(r)) categorized the interactions as being non-covalent in nature. The RGD peak distribution in the NCI analysis reveals the presence of van der Waals interactions, predominantly between the intercalator and DNA. Accordingly, we confirm that acridine/DNA interactions are relevant for understanding how the intercalator acts within nucleic acids. [Display omitted] • Acridine intercalates with DNA by non-covalent interactions on DFT studies. • The Binding energy showed that acridine interacts with DNA effectively. • The interactions with nitrogenous bases C-G and G-C were more effective than the bases A-T, TA. • The hydrogen bonds found were considered weak by the Quantum Theory of Atoms in Molecules. [ABSTRACT FROM AUTHOR]

Featured Application: Microfluidic device for high-throughput drug screening in a complex microenvironment of tumor tissue that allows rapid development of new antineoplastic agents. The aim of our research was to develop a numerical model of microflows occurring in the culture chambers (CC) of a microfluidic device of our construction for high-throughput drug screening. The incompressible fluid flow model is based on the lattice-Boltzmann equation, with an external body force term approximated by the He-Shan-Doolen scheme and the Bhatnagar-Gross-Krook approximation of the collision operator. The model accuracy was validated by the algebraic solution of the Navier–Stokes equation (NSE) for a fully developed duct flow, as well as experimentally. The mean velocity prediction error for the middle-length cross-section of CC was 1.0%, comparing to the NSE algebraic solution. The mean error of volumetric flow rate prediction was 6.1%, comparing to the experimental results. The analysis of flow hydrodynamics showed that the discrepancies from the plug-flow-like velocity profile are observed close to the inlets only, and do not influence cell cultures in the working area of CC. Within its workspace area, the biochip provides stable and homogeneous fully developed laminar flow conditions, which make the procedures of gradient generation, cell seeding, and cell-staining repeatable and uniform across CC, and weakly dependent on perturbations. [ABSTRACT FROM AUTHOR]

The recent spring up of the antineoplastic agents and the prolonged survival bring both challenge and chance to radiological practice. Radiological methods including CT, MRI and PET play an increasingly important role in evaluating the efficacy of these antineoplastic drugs. However, different antineoplastic agents potentially induce different radiological signs, making it a challenge for radiological response evaluation, which depends mainly on one-sided morphological response evaluation criteria in solid tumors (RECIST) in the status quo of clinical practice. This brings opportunities for the development of radiomics, which is promising to serve as a surrogate for response evaluations of anti-tumor treatments. In this article, we introduce the basic concepts of radiomics, review the state-of-art radiomics researches with highlights of radiomics application in predictions of molecular biomarkers, treatment response, and prognosis. We also provide in-depth analyses on major obstacles and future direction of this new technique in clinical investigations on new antineoplastic agents. [ABSTRACT FROM AUTHOR]

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo. These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents. [ABSTRACT FROM AUTHOR]

Inosine 5′‐monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3‐triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9–99.9% and 16–57%, respectively, at 10 μM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 μM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Many studies have shown that toxicities of anticancer drugs and their adverse effects are related to their chemical structure and high molecular weight that may result in a number of metabolites interacting with drug off-target networks. These factors require further attention for advancing cancer treatment and decreasing toxicities caused by the molecular complexity of antineoplastic agents. Providing more target-selective and tolerable cancer therapy with fewer side effects would not only improve patients’ compliance, but also would decrease cancer-remission rates. This review presents several antineoplastic agents and their metabolites with molecular weights greater than 500 g/mol, which reportedly cause more than fifteen types of adverse reactions during breast cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: Despite the remarkable progress in immune checkpoint blockade (ICB) therapy for cancer treatment, low objective response and immune‐related side effects (immune‐related adverse events, irAEs) limit the further development of ICBs. To address these challenges and enhance the efficiency of cancer immunotherapy, the emerging interest has focused on manipulating biomaterials to form innovational drug delivery systems that are necessary to effectively deliver immune checkpoint inhibitors. Such biomaterial‐based strategies can improve accumulation, control release, and enhance retention of checkpoint inhibitors within target locations while simultaneously reducing drug exposure for off‐target tissues, thereby optimizing both the efficacy and safety. In addition, with the assistance of biomaterials, combinations of ICB and conventional treatment strategies including chemotherapy, radiotherapy, and phototherapy are designed to further enhance the response rate of ICB. This review focuses on the latest reports on engineering biomaterials to improve the antitumor efficiency of ICB, with stress on antibody‐, gene‐, and trap protein–based immune checkpoint blockade strategies and their combinations with conventional therapies. Challenges and future trends in engineering biomaterials to modulate immune checkpoint therapy are discussed. [ABSTRACT FROM AUTHOR]

The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in electroceuticals, demonstrating for the first time the electrochemical activation of metal-based prodrugs. This is illustrated by the controlled activation of Pt(iv) prodrugs into their active Pt(ii) forms within a cellular context allowing selectivity and control of where, when and how much active drug is generated. [ABSTRACT FROM AUTHOR]

Abstract: The high mortality associated with oncological diseases is mostly due to tumors in advanced stages, and their management is a major challenge in modern oncology. Angiogenesis is a defined hallmark of cancer and predisposes to metastatic invasion and dissemination and is therefore an important druggable target for cancer drug discovery. Recently, because of drug resistance and poor prognosis, new anticancer drugs from natural sources targeting tumor vessels have attracted more attention and have been used in several randomized and controlled clinical trials as therapeutic options. Here, we outline and discuss potential natural compounds as salvage treatment for advanced cancers from recent and ongoing clinical trials and real‐world studies. We also discuss predictive biomarkers for patients' selection to optimize the use of these potential anticancer drugs. [ABSTRACT FROM AUTHOR]

Abstract: We conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database on spontaneously reported adverse events to evaluate the association between anticancer drug therapy and hepatitis B infection. Reports of hepatitis B infection were retrieved from the FAERS database. The reporting odds ratio (ROR) was used to estimate the association between hepatitis B infection and various anticancer agents and drug combinations. We detected statistically significant risk signals of hepatitis B for 33 of 64 anticancer agents by ROR (26 cytotoxicity drugs and seven molecular‐targeted drugs). We focused on molecular‐targeted drugs and assessed the risk of hepatitis B from specific anticancer drug combinations. The frequency of hepatitis B infection was significantly high for drugs such as rituximab, bortezomib, imatinib, and everolimus. The addition of cyclophosphamide, doxorubicin, and fludarabine to drug combinations additively enhanced the frequency of hepatitis B infection. There were no reports on hepatitis B infection associated with trastuzumab or azacitidine monotherapy. However, trastuzumab‐containing regimens (e.g., combinations with docetaxel or paclitaxel) were correlated with the incidence of hepatitis B infection, similar to azacitidine monotherapy. Our findings suggest that the concomitant use of anticancer drugs, such as trastuzumab, taxane, and azacitidine, may contribute to the risk of hepatitis B infection. The unique signals detected from the public database might provide clues to eliminate the threat of HBV in oncology. [ABSTRACT FROM AUTHOR]

Encorafenib (LGX818) is a promising BRAF V600E inhibitor that has efficacy against metastatic melanoma. To better understand its pharmacokinetics, we studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b −/− , Abcg2 −/− , and Abcb1a/1b;Abcg2 −/− mice, encorafenib was absorbed very quickly and to very high plasma levels, but without clear changes in oral availability between the strains. Upon oral or intravenous administration, encorafenib brain accumulation was markedly increased in Abcb1a/1b;Abcg2 −/− mice and to a lesser extent in Abcb1a/1b −/− mice. However, absolute brain concentrations and brain-to-plasma ratios remained very low in all strains, indicating intrinsically poor brain penetration of encorafenib. Upon intravenous administration, Abcb1a/1b;Abcg2 −/− mice showed somewhat reduced plasma elimination of encorafenib compared to wild-type mice, and lower accumulation of the drug in the intestinal tract, suggesting a limited role for these transporters in intestinal elimination of the drug. In Cyp3a −/− mice plasma levels of encorafenib were not markedly increased, suggesting a limited impact of Cyp3a on encorafenib oral availability. The low brain penetration of encorafenib might limit its efficacy against malignancies positioned behind a functional blood-brain barrier, but its oral bioavailability and distribution to other tested organs (liver, kidney, spleen, testis) was high. [ABSTRACT FROM AUTHOR]

Hypericum ascyron L. (Great St. Johnswort), which belongs to the Hypericaceae family, has been used for the treatment of hematemesis, metrorrhagia, rheumatism, swelling, stomach ache, abscesses, dysentery and irregular menstruation for >2,000 years in China. The aim of the present study was to clarify the anticancer activity compounds from H. ascyron L. and the underlying molecular mechanism. Anticancer activity of H. ascyron L. extract was evaluated using an MTT assay. To confirm the anticancer mechanism of activity compounds, Hoechst 33258, Annexin V‑fluorescein isothiocyanate/propidium iodide, 2',7'‑dichlorodihydrofluorescein diacetate, rhodamine 123 staining and caspase‑3 activity analysis were performed. The results demonstrated that the anti‑proliferative action of the mixture of kaempferol 3‑O‑β‑(2"‑acetyl) galactopyranoside (K) and quercetin (Q) (molar ratio, 1:1) was significantly increased compared with either of these two compounds separately, and the active fraction of the H. ascyron L. extract |(HALE). HALE, indicating that the anti‑proliferative function of H. ascyron L. may be a synergic effect of K and Q. Furthermore, the inhibitory effect of KQ on the growth of HeLa cells was mediated by the induction of apoptosis. To the best of our knowledge, the present study is the first to identify that KQ exhibits significant anti‑proliferation activity on HeLa cells via the apoptotic pathway, and is also the first to evaluate the anticancer potential of H. ascyron L. The results of the present study may provide a rational base for the use of H. ascyron L. in the clinic, and shed light on the development of novel anticancer drugs. [ABSTRACT FROM AUTHOR]

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT‑2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra‑pancreatic invasion, intra‑peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Nine novel 1-(4'-sulfamoylphenyl)-1,2,3-triazole derivatives bearing an N-heterocycle moiety were designed using a molecular hybridisation approach and synthesised by alkyne/azide click chemistry. Most of the synthesised compounds exhibited good to moderate antiproliferative activity (IC50 values 3.7 to 77.1 µM) against stomach, oesophagus and prostate cancer cell lines, but a compound containing an S-(2-pyridyl)thiomethyl moiety showed 10-fold greater activity against the stomach cell line than 5-fluorouracil. These results demonstrate that N-heterocycle-1,2,3-triazolylsulfonamides could be promising lead compounds to develop new antitumour drugs. [ABSTRACT FROM AUTHOR]

Mammalian cells, e.g., CHO, BHK, HEK293, HT-1080, and NS0 cells, represent important manufacturing platforms in bioengineering. They are widely used for the production of recombinant therapeutic proteins, vaccines, anticancer agents, and other clinically relevant drugs. HEK293 (human embryonic kidney 293) cells and their derived cell lines provide an attractive heterologous system for the development of recombinant proteins or adenovirus productions, not least due to their human-like posttranslational modification of protein molecules to provide the desired biological activity. Secondly, they also exhibit high transfection efficiency yielding high-quality recombinant proteins. They are easy to maintain and express with high fidelity membrane proteins, such as ion channels and transporters, and thus are attractive for structural biology and electrophysiology studies. In this article, we review the literature on HEK293 cells regarding their origins but also stress their advancements into the different cell lines engineered and discuss some significant aspects which make them versatile systems for biopharmaceutical manufacturing, drug screening, structural biology research, and electrophysiology applications. [ABSTRACT FROM AUTHOR]

Several anticancer drugs have been developed from natural products such as plants. Successful experiments in inhibiting the growth of human cancer cell lines using Saudi plants were published over the last three decades. Up to date, there is no Saudi anticancer plants database as a comprehensive source for the interesting data generated from these experiments. Therefore, there was a need for creating a database to collect, organize, search and retrieve such data. As a result, the current paper describes the generation of the Saudi anti-human cancer plants database (SACPD). The database contains most of the reported information about the naturally growing Saudi anticancer plants. SACPD comprises the scientific and local names of 91 plant species that grow naturally in Saudi Arabia. These species belong to 38 different taxonomic families. In Addition, 18 species that represent16 family of medicinal plants and are intensively sold in the local markets in Saudi Arabia were added to the database. The website provides interesting details, including plant part containing the anticancer bioactive compounds, plants locations and cancer/cell type against which they exhibit their anticancer activity. Our survey revealed that breast, liver and leukemia were the most studied cancer cell lines in Saudi Arabia with percentages of 27%, 19% and 15%, respectively. The current SACPD represents a nucleus around which more development efforts can expand to accommodate all future submissions about new Saudi plant species with anticancer activities. SACPD will provide an excellent starting point for researchers and pharmaceutical companies who are interested in developing new anticancer drugs. [ABSTRACT FROM AUTHOR]

The anthracyclines daunorubicin and doxorubicin are widely used antineoplastic agents due to their therapeutic activity against a broad variety of human cancers. Although, the classical model to explain anthracyclines’ cytotoxicity has been based in the direct interference with nucleic acid function, evidence suggests that the plasma membrane is also involved in the drug’s mechanism of action. In this work, the interaction of these drugs with two-dimensional membrane models were studied in order to gain further insights at the molecular level regarding anthracyclines membrane interactions. For that purpose, Langmuir monolayers composed of 1,2-dipalmitoyl- sn -glycero-3-phosphocholine (DPPC), sphingomyelin (SM) and cholesterol (Chol) were used, since these are the most common lipids found in biological membranes. Several biophysical techniques were employed: surface pressure (π) – area (A) isotherms measurements were used to investigate the adsorption and penetration of drugs, polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS) to acquire structural information and Brewster angle microscopy (BAM) to record images of the monolayers on the micrometer scale. The interactions of anthracyclines were assessed by alterations in the monolayers’ shape, characteristic parameters (C s −1 values and area per lipid molecule at 30 mN·m −1 and under maximum packing conditions) and morphology of each 2D model studied. The presence of the drugs in the interface led to the production of less ordered monolayers, as evidenced by the decrease in the compressibility modulus. In addition, the drugs’ effect on the membrane organization is related with their chemical structure and depends on the membraneś phase. For lower surface pressures, both electrostatic and hydrophobic interactions led to significant modifications in the monolayer order. With further compression, the impact of such interactions is reduced, resulting in the squeezing-out of some drug molecules from the interface. Furthermore, BAM images showed a clear anticancer drug interplay with the lipid monolayer by changes in the domains shape and appearance of bright dots, which are located in the frontier between the condensed and expanded lipid phases. [ABSTRACT FROM AUTHOR]

A new series of 3-allylseleno-6-alkylsulfonylpyridazines and 3-allylseleno-6-alkylsulfinylpyridazines were synthesized from 3,6-dichloropyridazine for anticancer agent development. The inhibitory effects of 3-allylseleno-6-alkylsulfonylpyridazines on human cancer cell lines were investigated. The synthesis involved thiolation, oxidation, selenylation, and Se-allylation of alkylthiols. That is, sodium methanethiolate, ethanethiol, propanethiol, butanethiol, pentanethiol, and hexanethiol were inserted into the 6-position of the pyridazine nucleus. These new synthetic compounds exhibited antiproliferative activity against human breast cancer (MCF-7), hepatocarcinoma (Hep3B), and human colon carcinoma (RKO) cells in CCK-8 assays, and are potential candidates for cancer chemotherapy. [ABSTRACT FROM AUTHOR]

A series of thiazole linked indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 13d displayed cytotoxicity of IC 50 = 93 nM towards DU145 cancer cell line. The most active compound 13d was also tested on RWPE-1 cells and was found to be safe compared to the DU145 cells. The target compounds were also evaluated for their inhibition activity of tubulin polymerization. Further, the treatment of compound 13d on DU145 cells led to the inhibition of cell migration ability. The detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 13d induced apoptosis in DU145 cells. The influence of the cytotoxic compound 13d on the cell cycle distribution was assessed on the DU145 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, the treatment with compound 13d caused collapse of mitochondrial membrane potential and elevated intracellular ROS levels in DU145 cells. The results from molecular modelling studies revealed that these compounds bind at the colchicine binding site of the tubulin. Thus, this new molecular scaffold could be a new lead for the development of anticancer agents that target tubulin. [ABSTRACT FROM AUTHOR]

Hollow fiber cell fishing (HFCF) based on human hepatoma cell HepG-2 or human renal tubular cell ACHN coupled with high performance liquid chromatography/ultraviolet detection (HPLC/UV) was developed and used for simultaneous study of the major antitumor active components in a formula of Yinchenhao decoction (YCHD) in vitro and in vivo , and in its constituent herbs, namely, Artemisia capillaris Thunb , Gardenia jasminoides Ellis, Radix et Rhizoma Rhei in vitro . Before application, chlorogenic acid, geniposide, p -hydroxyacetophenone, crocin and rhein were chosen as model compounds, the various validations, e.g., cell growth and cell viability on the fiber inner wall, binding between fiber active center and component, repeatability of retention time or relative peak area of the active components were investigated. We screened and identified the major antitumor active components of YCHD, verified their synergetic or antagonistic effect, correlated the major active components between in vitro and in vivo and determined major effective components. Our study will serve as a valuable reference in probing the antitumor material basis of YCHD and its three constituent herbs, as well as in identifying novel clinical aspects of traditional Chinese medicines. The results showed that HCFC-HPLC is a simple, rapid, and reliable method that simultaneously researches the interaction between multiple targets and multiple components of herbal medicine. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) proteins have emerged as important targets for anti-cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity. C5-modified SAHA analogs displayed dual selectivity to HDAC6 and HDAC8 over HDAC 1, 2, and 3, with only a modest reduction in potency. These findings are consistent with prior work showing that modification of the linker region of SAHA can alter isoform selectivity. The observed HDAC6/8 selectivity of C5-modified SAHA analogs provide guidance toward development of isoform selective HDAC inhibitors and more effective anti-cancer drugs. [ABSTRACT FROM AUTHOR]

The cancer community understands the value of blood profiling measurements in assessing and monitoring cancer. We describe an effort among academic, government, biotechnology, diagnostic, and pharmaceutical companies called the Blood Profiling Atlas in Cancer (BloodPAC) Project. BloodPAC will aggregate, make freely available, and harmonize for further analyses, raw datasets, relevant associated clinical data (e.g., clinical diagnosis, treatment history, and outcomes), and sample preparation and handling protocols to accelerate the development of blood profiling assays. [ABSTRACT FROM AUTHOR]

Oral antineoplastic agents provide convenience to the patient, but are accompanied by challenges distinct from parenteral cancer treatment. Challenges include a more complex pharmacokinetic profile, with food influencing the absorption of many agents. Standards for evaluating and labeling prandial implications on oral chemotherapy are inconsistent; studies to determine food effects should be conducted early, and potentially often, during drug development with standardization on how rational fasting or fed recommendations are presented in the package insert (PI). [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) modeling can be used to predict drug pharmacokinetics in virtual populations using models that integrate understanding of physiological systems. PBPK models have been widely utilized for predicting pharmacokinetics in clinically untested scenarios during drug applications and regulatory reviews in recent years. Here, we provide a comprehensive review of the application of PBPK in new drug application (NDA) review documents from the US Food and Drug Administration (FDA) in the past 4 years. [ABSTRACT FROM AUTHOR]

The targeted inhibition of epidermal growth factor receptor (EGFR) has represented a milestone in the treatment of lung cancer. Several studies convincingly and consistently demonstrated a significant superiority of EGFR-TKIs over standard platinum-chemotherapy in EGFR-mutated NSCLC patients, leading to the sequential approval of gefitinib, erlotinib and afatinib as new standard first-line clinical treatment. To date we are witnessing a second revolution in the management of EGFR-positive NSCLC thanks to the development of new treatment strategies aiming to overcome acquired resistance to TKIs and ultimately improve patients’ outcomes. In this review we summarize the most important recent findings regarding EGFR-inhibition in NSCLC, highlighting the current unsolved questions on the selection of the best TKI in first-line, which therapy can be combined with upfront EGFR-TKIs, how to overcome acquired resistance, and which are the clinical applications of liquid biopsy. [ABSTRACT FROM AUTHOR]

Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic. [ABSTRACT FROM AUTHOR]

The β-diketone scaffold is a key intermediate in the synthesis of COX-2 inhibitors, a type of non-steroidal anti-inflammatory agents of the coxib family, which have also been shown to have excellent anticancer potential at the preclinical stage of research. Moreover, it is also present in the family of natural products named curcuminoids. Both natural products and their synthetic analogues possess interesting antibacterial, neuroprotective and anticancer properties. Coordination compounds of curcuminoids with platinum-group metals as potential anticancer agents are a hot topic of current research, with most scientific articles on this topic having been published in the last five years. Structurally simpler diketones, such as acetylacetone derivatives, are also employed in the design of new metal-based agents. Most notably, the first metal-based, non-platinum anticancer compound to enter clinical trials was budotitane - cis-diethoxy(1-phenylbutane-1,3-dionato)titanium(IV). Recently, several studies of platinum-group coordination and organometallic compounds, their biological evaluation and mode-of-action studies have been published in high-impact journals in the field of inorganic and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Structures containing 8-hydroxyquinoline scaffold are useful for anticancer drug development. The title ester (5-chloroquinolin-8-yl)-2-fluorobenzoate was prepared by the reaction of 2-fluorobenzoyl chloride with 5-chloro-8-hydroxyquinoline. The structure of the title compound was assigned by diverse spectroscopic techniques. Moreover, a crystallographic study was undertaken and its supramolecular characteristics were analyzed. Thus, the central ester fragment C8/O1/C10(O2)/C11 is almost planar with a root mean square (r.m.s.) deviation of 0.0612 Å and it makes dihedral angles of 76.35(6)° and 12.89(11)°, with quinoline and phenyl rings respectively. The structure shows C-H...X (X = halogen) non-classical hydrogen bonds. It also has a halogen . . . halogen distance less than the sum of the van derWaals radii (3.2171(15) Å). As a result of interactions with halogen atoms, chains of centrosymmetric dimer that form edge-fused R22(18) rings run parallel to the plane (100). [ABSTRACT FROM AUTHOR]

Drug resistance remains a major clinical obstacle to successful treatment of cancer. As posttranslational modification is becoming widely recognized to affect the function of oncoproteins, targeting specific posttranslational protein modification provides an attractive strategy for anticancer drug development. CD147 is a transmembrane glycoprotein contributing to chemo-resistance of cancer cells in a variety of human malignancies. Ubiquitination is an important posttranslational modification mediating protein degradation. Degradation of oncoproteins, CD147 included, emerges as an attractive alternative for tumor inhibition. However, the ubiquitination of CD147 remains elusive. Here in this study, we found that deletion of the CD147 intracellular domain (CD147-ICD) prolonged the half-life of CD147 in HEK293T cells, and we identified that CD147-ICD interacts with FBXO22 using mass spectrometry and Western blot. Then, we demonstrated that FBXO22 mediates the polyubiquitination and degradation of CD147 by recognizing CD147-ICD. While knocking down of FBXO22 prolonged the half-life of CD147 in HEK293T cells, we found that FBXO22 regulates CD147 protein turnover in SMMC-7721, Huh-7 and A549 cells. Moreover, we found that the low level of FBXO22 contributes to the accumulation of CD147 and thereafter the cisplatin resistance of A549/DDP cells. To conclude, our study demonstrated that FBXO22 mediated the polyubiquitination and degradation of CD147 by interacting with CD147-ICD, and CD147 polyubiquitination by FBXO22 reversed cisplatin resistance of tumor cells. [ABSTRACT FROM AUTHOR]

Inappropriate activation of c-mesenchymal-epithelial transition (MET), the receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and represented a promising therapeutic target for developing anticancer agents. In contrast to other solid tumors, there are limited data describing the functional role of HGF/c-MET signaling pathway in lymphoma. In the current review, we summarize recent findings about the expression, cellular mechanisms/functions, and therapeutic application of HGF/c-MET in different types of lymphoma, especially B cell lymphoma, T and NK cell lymphoma, and Hodgkin lymphoma. We also discuss the existing problems and future directions about studying the HGF/c-MET pathway in lymphoma cells. [ABSTRACT FROM AUTHOR]

By means of limited proteolysis assay, three-dimensional NMR, X-ray crystallography and alanine mutations, a dynamic region at the Q221R222N223 motif in the Bcl-2 homology 3 (BH3) domain of Mcl-1 has been identified as a conformational switch which controls Mcl-1 ubiquitination. NoxaBH3 binding biases the QRN motif toward a helical conformation, thus leading to an enhanced in vitro ubiquitination of Mcl-1. In contrast, BimBH3 binding biases the QRN motif toward a nonhelical conformation, thus leading to the inhibition of ubiquitination. A dual function Mcl-1 inhibitor, which locates at the BH3 domain of Mcl-1 and forms hydrogen bond with His224 to drive a helical QRN conformation, so that it not only interferes with the pro-apoptotic partners, but also facilitates Mcl-1 ubiquitination in living cells, is described. As a result, this inhibitor manifests a more effective apoptosis induction in Mcl-1-dependent cancer cells than other inhibitors exhibiting a similar binding affinity with it. [ABSTRACT FROM AUTHOR]

It was the first time that 3-octadecylcarbamoylacrylicacid-cisplatin nanocomplexes (OMI-CDDP-N) were synthesized via monocarboxylato and O→Pt coordination. The nanocomplexes exhibited lower IC50values compared with cisplatin (CDDP)in vitro, and enhanced antitumor efficacy in murine liver cancer (H22)in vivo. However, the toxicity of the nanocomplexes was more severe than CDDP. OMI-CDDP-N-based liposome (OCP-L) was prepared in order to maintain the efficacy and reduce the toxicity of OMI-CDDP-N. Here, a series of parameters were investigated to optimize liposome formulation. The optimal formulation was CDDP/phospholipids/cholesterol (1/10/0.7 wt.%), with distilled water as hydration medium and an encapsulation efficiency of 94.2 ± 2.1%.In vitrocytotoxicity studies revealed that OCP-L and OMI-CDDP-N exhibited a lower IC50compared with commercial cisplatin injection (CDDP-S) in a variety of human cancer cells. In H22-implanted mice, OCP-L showed a significantly higher antitumor activity than OMI-CDDP-N or CDDP-S at a dose of 5 mg/kg (p < 0.01). Moreover, OCP-L exceeded the size cutoff for kidney clearance, hence it bypassed the nephrotoxicity of CDDP which is a major curse of CDDP in the clinic. These results suggested that the unique OMI-CDDP-N-entrapped liposome can overcome the disadvantages associated with conventional CDDP therapy and provide a higher safety profile. [ABSTRACT FROM AUTHOR]

A major focus of contemporary drug screening strategies is the identification of novel anticancer compounds, which often results in underutilization of resources. Current drug evaluation involves in vivo tumor (xenograft) regression as proof‐of‐principle for cytotoxicity (POC). However, this end-point lacks any assessment of drug resistance of the residual tumor and its capability to establish refractory and/or recurrent disease, which would represent more appropriate indicators of therapeutic failure. We have recently developed a flow cytometry-based approach for the analyses of intra-tumor cellular heterogeneity across stem cell hierarchies, genetic instability and differential cell cycling fractions, which can potentially be predictive of refractory disease and tumor relapse. Iterating this approach after initial POC screening in the drug discovery pipeline would have a great impact in terms of precision of drug evaluation, design of optimal drug combinations and/or drug repositioning. In this perspective, we highlight how through embracing of a comprehensive, informative and analytical assessment of the cellular content of residual tumors, the fidelity and statistical robustness of preclinical drug discovery can be greatly improved. [ABSTRACT FROM AUTHOR]

Improvement of antineoplastic activity and selectivity is a main goal in the development of antineoplastic agents. Herein, we synthesized three new iridium (III) complexes: [Ir(ppy) 2 (FTTP)](PF 6) (Ir1 , ppy = 2-phenylpyridine, FTTP = 2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene), [Ir(bzq) 2 (FTTP)](PF 6) (Ir2 , bzq = benzo[ h ]quinolone), [Ir(piq) 2 (FTTP)](PF 6) (Ir3 , piq = 1-phenylisoquinoline). Ir1-3 exhibit excellent cytotoxicity against various cancer cells particularly towards human cervical carcinoma HeLa cells while remaining non-toxic to normal cell lines. Assays on 2D cell colony formation and 3D multicellular tumor spheroid model confirm that Ir1-3 can effectively inhibit the colony-forming and penetrate deeply into HeLa 3D multicellular tumor spheroid model exhibiting a notable cytotoxic effect, which was consistent with the results from the viability assays. Meanwhile, confocal microscopy shows a rapid uptake of Ir1-3 and co-localization experiments with subcellular markers reveal that Ir1-3 locate mainly at the mitochondria. Further investigation of the mechanism indicated the complexes Ir1-3 promote the excessive generation of ROS, inhibit glutathione and thioredoxin reductase that effectively interferes with the intracellular redox balance, induce oxidative stress and result in caspase-dependent apoptosis. Moreover, the ROS-mediated inactivation of the PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway, DNA damage combing with suppression of the cyclin D1/CDK4/6 activity arrested cell cycle in the G0/G1 phase are involved in complexes-induced cell apoptosis. Finally, assays on xenografted cervical carcinoma mouse model confirm the excellent biocompatibility and antineoplastic efficiency of Ir3 in vivo. Collectively, this work offers building blocks for developing iridium (III) complexes as clinical application potential. Three new iridium(III) complexes were synthesized and characterized. The anticancer activity of the complexes was investigated. Complex [Ir(piq) 2 (FTTP)](PF 6) (FTTP = 2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene, piq = 1-phenylisoquinoline) can effectively inhibit the tumor growth with an inhibitory rate of 54.8%. [Display omitted] • Three new iridium(III) complexes were synthesized and cytotoxicity in vitro and in vivo was studied. • Apoptosis, reactive oxygen species, colony formation, cell cycle arrest were studied. • The location and mitochondrial membrane potential were explored. • The intracellular glutathione, malondialdehyde and thioredoxin reductase were performed. • The expression of B-cell lymphoma-2 family proteins was assayed. [ABSTRACT FROM AUTHOR]

[Pd(FLU)X]· yHO· zCHOH (FLU = flubendazole; X = Cl ( 1), y = 0, z = 0; X = Br ( 2), NO ( 3), y = 2, z = 0; X = SCN ( 4), y = 2, z = 3) were synthesized as potential anticancer complexes, and their structures were elucidated using elemental analysis, TG/DTA, IR, H NMR, UV-vis., and conductivity measurements. FLU interacts with Pd(II) ions as a neutral unidentate ligand via the pyridine-type nitrogen of the benzimidazole ring. Geometry optimization, molecular electrostatic potential maps and natural bond orbital analysis were performed by DFT/B3LYP method. FLU, in comparison to its complexes, was screened for its antibacterial and cytotoxic activity. Complexes 1-4 possess strong anticancer activity with IC values (4.13-3.68 μg ml) compared with 3.57 μg ml reported for cis-platin. The cytotoxicity was shown to be affected by the nature of the anion, where the sequence is 3 > 2 > 4 > 1 in case of MCF7 cell line. Structural-activity relationships suggested that E , energy gap and dipole moment were the most significant descriptors for the correlation with the antitumor activity. [ABSTRACT FROM AUTHOR]

A novel series of sulfonamide derivatives 4–21 have been synthesized starting from the strategic starting material ( E )-4-Chloro- N -(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide 4 . Two series of hydrazone 5–9 , and pyridone 10–21 derivatives bearing a sulfonamide moiety were obtained. All the newly synthesized compounds were evaluated for their in vitro cytotoxic activity against human liver cancer cell line (HepG2). Compounds 4–6, 8, 9, 10–14 and 16–18 showed higher activity compared to doxorubicin as a positive control. The radiosensitizing ability of the most promising compounds 4, 10 and 12 was studied which showed an increase in the cell killing effect of γ-radiation after combination with these derivatives. The molecular design was performed to predict the binding mode of the most promising compounds 4, 10 and 12 with the active site of hCA IX, that showed appropriate fitting with the relevant amino acids in the binding pocket on the basis of standard bond lengths, angles, S score and E conformation data. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. Liphagal, isolated from the marine sponge Aka coralliphaga, possesses the special "liphagane" meroterpenoid carbon skeleton and has been demonstrated as a PI3Kα inhibitor. Molecular docking and molecular dynamics simulations were performed to explore the dynamic behaviors of PI3Kα binding with liphagal, and free energy calculations and energy decomposition analysis were carried out by use of molecular mechanics/Poisson-Boltzmann (generalized Born) surface area (MM/PB(GB)SA) methods. The results reveal that the heteroatom rich aromatic D-ring of liphagal extends towards the polar region of the binding site, and the D-ring 15-hydroxyl and 16-hydroxyl form three hydrogen bonds with Asp810 and Tyr836. The cyclohexyl A-ring projects up into the upper pocket of the lipophilic region, and the hydrophobic/van der Waals interactions with the residues Met772, Trp780, Ile800, Ile848, Val850, Met922, Phe930, Ile932 could be the key interactions for the affinity of liphagal to PI3Kα. Thus, a new strategy for the rational design of more potent analogs of liphagal against PI3Kα is provided. Our proposed PI3Kα/liphagal binding mode would be beneficial for the discovery of new active analogs of liphagal against PI3Kα. [ABSTRACT FROM AUTHOR]

In 80-90% tumor cells, telomerase becomes active and stabilizes the length of telomeres. The formation and stabilization of G-quadruplexes formed from human telomeric sequences have been proved able to inhibit the activity of telomerase, thus human telomeric G-quadruplex structure has become a potential target for the development of cancer therapy. Hence, structure of G-quadruplex formed in K+ solution has been an attractive hotspot for further studies. However, the exact structure of human telomeric G-quadruplex in K+ is extremely controversial, this study provides information for the understanding of different G-quadruplexes. Here, we report that 22nt and 24nt human telomeric sequences form unimolecular hybrid-type mixed parallel/antiparallel G-quadruplex in K+ solution elucidated utilizing Circular Dichroism, Differential Scanning Calorimetry, and gel electrophoresis. Moreover, individual configuration of these two sequences was speculated in this study. The detailed structure information of the G-quadruplex formed under physiologically relevant condition is necessary for structure-based rational drug design. [ABSTRACT FROM AUTHOR]