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With high incidence of hepatocarcinoma and limited effective treatments, most patients suffer in pain. Antitumor drugs are single-targeted, toxicity, causing adverse side effects and resistance. Dihydroartemisinin (DHA) inhibits tumor through multiple mechanisms effectively. This study explores and evaluates safety and potential mechanism of DHA towards human hepatocarcinoma based on network pharmacology in a comprehensive way. Adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of DHA were evaluated with pkCSM, SwissADME, and ADMETlab. Potential targets of DHA were obtained from SwissTargetPrediction, Drugbank, TargetNET, and PharmMapper. Target gene of hepatocarcinoma was obtained from OMIM, GeneCards, and DisGeNET. Overlapping targets and hub genes were identified and analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway. Molecular docking was utilized to investigate the interactions sites and hydrogen bonds. Cell counting kit-8 (CCK8), wound healing, invasion, and migration assays on HepG2 and SNU387 cell proved DHA inhibits malignant biological features of hepatocarcinoma cell. DHA is safe and desirable for clinical application. A total of 131 overlapping targets were identified. Biofunction analysis showed targets were involved in kinase activity, protein phosphorylation, intracellular reception, signal transduction, transcriptome dysregulation, PPAR pathway, and JAK-STAT signaling axis. Top 9 hub genes were obtained using MCC (Maximal Clique Centrality) algorithm, namely CDK1, CCNA2, CCNB1, CCNB2, KIF11, CHEK1, TYMS, AURKA, and TOP2A. Molecular docking suggests that all hub genes form a stable interaction with DHA for optimal binding energy were all less than - 5 kcal/mol. Dihydroartemisinin might be a potent and safe anticarcinogen based on its biological safety and effective therapeutic effect., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Proteolysis targeting chimeras (PROTACs) can use the intrinsic protein degradation system in cells to degrade pathogenic target proteins, and are currently a revolutionary frontier of development strategy for tumor treatment with small molecules. However, the poor water solubility, low cellular permeability, and off-target side effects of most PROTACs have prevented them from passing the preclinical research stage of drug development. This requires the use of appropriate delivery systems to overcome these challenging hurdles and ensure precise delivery of PROTACs towards the tumor site. Therefore, the combination of PROTACs and multifunctional delivery systems will open up new research directions for targeted degradation of tumor proteins. In this review, we systematically reviewed the design principles and the most recent advances of various PROTACs delivery systems. Moreover, the constructive strategies for developing multifunctional PROTACs delivery systems were proposed comprehensively. This review aims to deepen the understanding of PROTACs drugs and promote the further development of PROTACs delivery system., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xupeng Mu reports financial support was provided by the Science and Technology Development Plan Projects of Jilin Province. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neurotoxicity is a common side effect of certain types of therapeutic drugs, posing a major hurdle for their clinical application. Accumulating evidence suggests that ferroptosis is involved in the neurotoxicity induced by these drugs. Therefore, targeting ferroptosis is considered to be a reasonable approach to prevent such side effect. Arctigenin (ATG) is a major bioactive ingredient of Arctium lappa L., a popular medicinal plant in Asia, and has been reported to have multiple bioactivities including neuroprotection. However, the mechanisms underlying the neuroprotection of ATG has not been well elucidated. The purpose of this study was to investigate whether the neuroprotection of ATG was associated with its ability to protect neuronal cells from ferroptosis. Using neuronal cell ferroptosis model induced by either classic ferroptosis induces or therapeutic drugs, we demonstrated for the first time that ATG in the nanomolar concentration range effectively prevented neuronal cell ferroptosis induced by classic ferroptosis inducer sulfasalazine (SAS) and erastin (Era), or therapeutic drug oxaliplatin (OXA) and 5-fluorouracil (5-FU). Mechanistically, we uncovered that the anti-ferroptotic effect of ATG was attributed to its ability to activate SLC7A11-cystine-cysteine axis. The findings of the present study implicate that ATG holds great potential to be developed as a novel agent for preventing SLC7A11 inhibition-mediated neurotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Germline BRCA mutations (gBRCAm) occur in 4%-8% patients with metastatic pancreatic cancer (mPC); guidelines recommend platinum-based chemotherapies and olaparib maintenance in this population. We evaluated, through modeling, the role of treatments and gBRCA testing on health outcomes of mPC patients., Methods: A decision tree/partitioned survival model was developed to assess lifetime health outcomes for four strategies: 1) no testing; 2) early testing/no olaparib maintenance; 3) early testing (i.e., before 1L treatment)/olaparib maintenance; and 4) late testing/olaparib maintenance. Treatment patterns were assumed to follow current practice in the United States. Overall survival and progression-free survival curves were extrapolated from pivotal trials, including POLO trial for outcomes from olaparib maintenance after at least 16 weeks of platinum-based chemotherapy., Results: Among patients with gBRCAm, almost twice as many patients received platinum-based regimens in strategies involving early testing compared to when early testing was not employed (78.7 % vs 40.2 %). Health outcomes were highest in the strategy with early testing and available olaparib treatment whether considering progression-free life years (PF LYs, 1.27 vs 0.55-0.87), LYs (1.82 vs 0.95-1.27) or quality adjusted life years (QALYs, 1.15 vs 0.73-0.92 for others). Consistent patterns of results were observed in the overall cohort of mPC patients (i.e., irrespective of gBRCAm)., Conclusion: Patients with mPC achieved longest health outcomes (as measured by mean PF LYs, LYs and QALYs) with a scenario of early gBRCA testing and availability of olaparib maintenance. The results were primarily driven by improved health outcomes associated with higher efficacy of platinum-based chemotherapies and olaparib used in gBRCAm patients., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Aim: Cinchonine (CN) and its isomer cinchonidine (CD), two of the common cinchona alkaloids, are wildly used as antimalarial drugs. However, the effects of CN and CD on the auditory system are unknown., Methods: Molecular docking and molecular dynamics (MD) simulation were used for predicting effective drugs. The CCK-8 assay was conducted for assessing cell viability in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. MitoSox Red staining revealed reactive oxygen species (ROS) amounts. TMRM staining was used to assess the mitochondrial membrane potential (ΔΨm). Immunofluorescence staining of myosin 7a was used to examine hair cells (HCs) in cisplatin-treated neonatal mouse cochlear explants, while TUJ-1 immunostaining was used for the detection of spiral ganglion neurons (SGNs). Cleaved caspase-3 and TUNEL immunostaining were utilized for apoptosis assessment. Immunoblot was carried out to detect PI3K-AKT signaling effectors., Results: Pretreatment with CN or CD significantly increased cell viability and reduced mitochondrial dysfunction and ROS accumulation in cisplatin-treated HEI-OC1 cells. Immunofluorescent staining of cochlear explants showed that CN and CD attenuated cisplatin-induced damage to SGNs and HCs. Immunoblot revealed that CN and CD downregulated the expression of cleaved caspase-3 and activated PI3K-AKT signaling in cisplatin-injured HEI-OC1 cells., Conclusion: CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin-associated hearing loss., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC., (© 2023. The Author(s).)

Oxaliplatin (Oxa) is one of the most effective chemotherapeutic drugs used in the treatment of colorectal cancer (CRC). However, the use of this drug is associated with severe side‑effects and patients eventually develop resistance to Oxa. In recent years, copper complexes have been extensively investigated as substitutes for platinum‑based drugs. Therefore, a number of copper complexes have also been developed for cancer therapy, such as copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)]. In the present study, the antitumor activity and the related molecular mechanisms of Cu(sal)(phen) were examined in CRC cells. As compared with the chemotherapeutic drug, Oxa, Cu(sal)(phen) was more effective in inducing apoptosis and reactive oxygen species (ROS) production, and in decreasing mitochondrial membrane potential in the CRC cell lines, HCT116 and SW480. In addition, the expression of the apoptosis‑related proteins, Bcl‑2 and survivin, and those of the upstream regulators, p‑JAK2 and p‑STAT5, were significantly decreased in the two cell lines following treatment with Cu(sal)(phen). Furthermore, the efficacy of the complex against CRC was found to be excellent in an animal model. The results of immunohistochemical analysis revealed that the expression levels of Bcl‑2, survivin and Ki‑67 in tumor tissues were decreased following Cu(sal)(phen) treatment. The antitumor mechanisms underlying Cu(Sal)(phen) treatment were the induction of ROS generation, the inhibition of the JAK2/STAT5 signaling pathway and the downregulation of the expression of anti‑apoptotic proteins, such as Bcl‑2 and survivin. On the whole, the findings of the present study indicated that Cu(sal)(phen) effectively inhibited the viability and proliferation of HCT116 and SW480 CRC cells; in the future, the authors aim to conduct further experiments in future studies to provide more evidence that supports the development of Cu(sal)(phen) as a therapeutic agent for CRC.

Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Poly(ADP-ribose) polymerase inhibitor maintenance treatments are available for platinum-sensitive advanced ovarian cancer. Olaparib (O) is available for BRCA mutation patients or in combination with bevacizumab (O+B) for patients with homologous recombination deficiency (HRD+); niraparib (N) is available for all patients., Objective: This study aimed to evaluate the cost effectiveness of biomarker testing and maintenance treatments (mTx) with poly(ADP-ribose) polymerase inhibitor in platinum-sensitive advanced ovarian cancer in the USA., Patients and Methods: Ten strategies were evaluated (S1-S10), representing biomarker testing (none, BRCA or HRD), and mTx (O, O+B, N or B). PAOLA-1 data were used to build a model estimating progression-free survival (PFS), second PFS (PFS2) and overall survival for O+B. PFS was modelled through mixture cure models; PFS2 and overall survival were modelled by standard parametric models. Hazard ratios of PFS for O+B versus B, N and O were obtained from the literature to estimate PFS for B, N and O. PFS2 and OS for B, N and O were informed by PFS benefits., Results: S2 (no testing, B) had the lowest cost while S10 (HRD testing, O+B for HRD+ and B for HRD-) had the highest quality-adjusted life-years (QALYs). All niraparib strategies were dominated. S2, S4 (BRCA testing, O for BRCA+ and B for BRCA-), S6 (BRCA testing, olaparib plus bevacizumab for BRCA+ and bevacizumab for BRCA-) and S10 were the non-dominated strategies with an incremental cost-effectiveness ratio of $29,095/QALY, $33,786/QALY and $52,948/QALY for S4 versus S2, S6 versus S4 and S10 versus S6, respectively., Conclusions: Homologous recombination deficiency testing followed by O+B for HRD+ and B for HRD- is a highly cost-effective strategy for patients with platinum-sensitive advanced ovarian cancer. A HRD biomarker-guided approach provides most QALYs with good economic value., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.)

In the present study, we investigated the antitumor effect and associated molecular mechanisms of the copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)] against hepatocellular carcinoma (HCC). Cu(sal)(phen) inhibited the proliferation of HCC cells (HepG2 and HCC-LM9) and induced apoptosis of HCC cells in a dose-dependent manner by upregulating mitochondrial reactive oxygen species (ROS) production. The expression of the antiapoptotic proteins survivin and Bcl-2 was decreased, while the expression of the DNA damage marker γ-H 2 AX and the apoptotic marker cleaved PARP was upregulated with Cu(sal)(phen) treatment. In vivo, the growth of HepG2 subcutaneous xenograft tumors was greatly attenuated by Cu(sal)(phen) treatment. Immunohistochemistry staining showed that the expression of survivin, Bcl-2, and Ki67 in the tumor was downregulated by Cu(sal)(phen). Toxicity experiments with BALB/c mice revealed that Cu(sal)(phen) is a relatively safe drug. Our results indicate that Cu(sal)(phen) possesses great potential as a therapeutic drug for HCC., (© 2023 Wiley Periodicals LLC.)

5,7-Dihydroxy-4-methylcoumarin (D4M) is attributed to free radical scavenging effects, with wide application for anti-oxidation. This work aimed to assess D4M's impact on cisplatin-induced ototoxicity. The cell viability was estimated with CCK-8 assay. Apoptosis was detected by the Annexin V-FITC and PI assay. The reactive oxygen species (ROS) level was determined by MitoSOX-Red and CellROX-Green probes. Mitochondrial membrane potential was analyzed with TMRM staining. Immunofluorescence was utilized for hair cells and spiral ganglion neuron detection. Apoptosis-associated proteins were assessed by cleaved caspase-3 and TUNEL staining. These results showed that D4M pretreatment protected hair cells from cisplatin-induced damage, increased cell viability, and decreased apoptosis in House Ear Institute-Organ of Corti1 (HEI-OC1) cells and neonatal mouse cochlear explants. D4M significantly inhibited cisplatin-induced mitochondrial apoptosis and reduced ROS accumulation. In addition, the protective effect of D4M on cisplatin-induced ototoxicity was also confirmed in cochlear hair cells and spiral ganglion neurons in neonatal mice. Mechanistic studies showed that D4M markedly downregulated p-JNK and elevated the expression ratio of p-FoxO1/FoxO1, thereby reducing cisplatin-induced caspase-dependent apoptosis. Meanwhile, D4M-related protection of HEI-OC1 cells was significantly blunted by JNK signaling induction with anisomycin. This study supports the possibility that D4M may be used as a new compound to prevent cisplatin-related hearing loss., Competing Interests: Declaration of competing interest The authors declare that no competing interests exist., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To explore whether apatinib can reverse the chemotherapy resistance of patients with advanced sarcoma. Methods: The clinical data of advanced sarcoma patients after chemotherapy who received the original chemotherapy regimen combined with low-dose apatinib in Cancer Center of Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology from May 2018 to November 2021 were collected retrospectively to evaluate the efficacy and safety of this regimen. The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and adverse events (AE). The patients were grouped according to the diagnosis: osteosarcoma, soft tissue sarcoma and undifferentiated small round cell sarcoma. And the benefits of combination treatment was investigated with the stratified analysis of best outcome of combined therapy, lines of chemotherapy received, best response and PFS of original chemotherapy. Results: A total of 30 patients were included in this study, including 20 males and 10 females. The mean age was (25.6±14.7) years. There were 9 cases of osteosarcoma, 11 cases of soft tissue sarcoma and 10 cases of undifferentiated small round cell sarcoma. No patient achieved complete response, 8 patients (26.7%) achieved partial response, 19 patients (63.3%) achieved disease stability, the ORR was 26.7%(8/30), and the DCR was 90.0%(27/30). The median PFS and OS were 4.1 and 13.1 months respectively. Among the three different subtypes of sarcoma, the ORR of osteosarcoma was 44.4% (4/9), the median PFS was 4.1 months, and the median OS was not yet achieved; the ORR of undifferentiated small round cell sarcoma was 40% (4/10), the median PFS was 6.4 months, and the median OS was 10.9 months; No response was observed in soft tissue sarcoma, and the median PFS and median OS was 3.5 and 7.3 months respectively. Patients who achieved objective response had better PFS than patients with stable disease (12.8 vs 3.8 months, P =0.015), and patients with PFS≥ 6 months of original chemotherapy had better PFS benefits (12.7 vs 2.7 months, P <0.001). However, the number of original chemotherapy lines and the best response of original chemotherapy had no significant effect on the PFS of this combination regimen. In terms of safety, the related toxicity of apatinib was no more than grade 2, and the grade 4 chemotherapy-related adverse reactions was mainly hematological toxicity, of which 2 patients interrupted treatment because of febrile neutropenia. Conclusion: Low dose apatinib is effective in reversing chemotherapy resistance of osteosarcoma and undifferentiated small round cell sarcoma with acceptable adverse reactions.

The continuous development of antineoplastic therapy has significantly reduced the mortality of patients with malignant tumors, but its induced cardiotoxicity has become the primary cause of long-term death in patients with malignant tumors. However, the pathogenesis of cardiotoxicity of antineoplastic therapy is currently unknown, and practical means of prevention and treatment are lacking in clinical practice. Therefore, how to effectively prevent and treat cardiotoxicity while treating tumors is a major challenge. Animal models are important tools for studying cardiotoxicity in antitumor therapy and are of great importance in elucidating pathophysiological mechanisms and developing and evaluating modality drugs. In this paper, we summarize the existing animal models in antitumor therapeutic cardiotoxicity studies and evaluate the models by observing the macroscopic signs, echocardiography, and pathological morphology of the animals, aiming to provide a reference for subsequent experimental development and clinical application., Competing Interests: There is no conflict of interest among the authors., (Copyright © 2022 Chenchen Meng et al.)

Background: Chemotherapy can induce premature ovarian insufficiency (POI). POI causes multiple sequelae and is currently incurable. As shown in our previous studies, systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) home to ovaries with chemotherapy-induced POI and subsequently reduce ovarian injury and improve ovarian function in rats with POI. However, the cellular mechanisms that direct the migration and homing of hAD-MSCs to ovaries with chemotherapy-induced POI are incompletely understood. This study investigated the role of the SDF-1/CXCR4 axis in the migration and homing of systemically transplanted hAD-MSCs to ovaries with chemotherapy-induced POI and its relevant downstream signalling pathways., Methods: CXCR4 expression in hAD-MSCs was assessed using Western blotting and immunofluorescence staining. hAD-MSC migration was tested using Transwell migration assays. SDF-1 levels were detected using ELISA. Seventy-two female SD rats were randomly divided into the control, POI, hAD-MSCs and hAD-MSCs + AMD3100 groups. Cyclophosphamide was used to establish rat POI models. For inhibitor treatment, hAD-MSCs were pretreated with AMD3100 before transplantation. PKH26-labeled hAD-MSCs were injected into the tail vein of POI rats 24 h after chemotherapy. After hAD-MSC transplantation, the homing of hAD-MSCs to ovaries and ovarian function and pathological changes were examined. We further investigated the molecular mechanisms by detecting the PI3K/Akt and ERK1/2 signalling pathways., Results: hAD-MSCs expressed CXCR4. SDF-1 induced hAD-MSC migration in vitro. SDF-1 levels in ovaries and serum were significantly increased in rats with chemotherapy-induced POI, and ovaries with POI induced the homing of hAD-MSCs expressing CXCR4. Blocking the SDF-1/CXCR4 axis with AMD3100 significantly reduced the number of hAD-MSCs homing to ovaries with POI and further reduced their efficacy in POI treatment. The binding of SDF-1 to CXCR4 activated the PI3K/Akt signalling pathway, and LY294002 significantly inhibited hAD-MSC migration induced by SDF-1 in vitro. Moreover, inhibition of the PI3K/Akt signalling pathway significantly reduced the number of systemically transplanted hAD-MSCs homing to chemotherapy-induced ovaries in rats with POI., Conclusions: SDF-1/CXCR4 axis partially mediates the migration and homing of systemically transplanted hAD-MSCs to the ovaries of rats with chemotherapy-induced POI, and the PI3K/Akt signalling pathway might be involved in the migration and homing of hAD-MSCs mediated by the SDF-1/CXCR4 axis., (© 2022. The Author(s).)

The tetralone and tetralone derivatives, as crucial structural scaffolds of potential novel drugs targeted at multiple biological end-points, are normally found in several natural compounds and also, it can be used as parental scaffold and/or intermediate for the synthesis of a series of pharmacologically active compounds with a broad-spectrum of bioactivities including antibacterial, antitumor, CNS effect and so on. Meanwhile, SAR information of its analogues has drawn attentions among medicinal chemists, which could contribute to the further research related to tetralone derivatives aimed at multiple targets. This review encompasses pharmacological activities, SAR analysis and docking study of tetralone and its derivatives, expecting to provide a general retrospect and prospect on tetralone derivatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Overexpressed P-glycoprotein (P-gp), as the key factor in multidrug resistance (MDR), can greatly reduce intracellular drug levels as a result of chemotherapeutic drug efflux out of cancer cells. Although various P-gp antagonists have been developed to circumvent the MDR effect, the common strategies of physical entrapment or chemical conjugation of anticancer drugs may inevitably induce unstable circulation in vivo or poor response in cancer cells, greatly limiting the therapeutic efficacy. Herein a double-drug-based supramolecular complex (DDSC) was first constructed based on the host-guest interactions between two active drugs, curcumin (Cur)-bridged bis(β-cyclodextrin) and ferrocene-linked camptothecin (CPT). Supramolecular dual drug nanomicelles (SDDNMs) formed by the DDSC self-assembly are proposed to work against the MDR effect, in which Cur as a P-gp antagonist in combination with CPT realized stable transport in vivo and efficient stimuli-responsiveness in cells. In vitro and in vivo studies further confirmed that SDDNMs effectively circumvented the drug efflux induced by the MDR effect and remarkably enhanced the synergistic therapeutic effects.

The development of chemoresistance is the major cause of treatment failure in nasopharyngeal carcinoma (NPC). Although 'paradoxical' activation of extracellular signal-regulated kinase (ERK) has been shown to contribute resistance to anticancer treatment, the role of ERK in NPC chemoresistance has not been yet revealed. In this work, we report that trametinib, a clinically available mitogen-activated protein kinase inhibitor for melanoma treatment, overcomes NPC chemoresistance via suppressing ERK activation induced by chemotherapy. We first showed that trametinib at nanomolar concentrations was active against NPC cells and acted synergistically with cisplatin. Trametinib remarkably decreased phosphorylation of ERK and its downstream effector in NPC cells. We next showed that cisplatin treatment stimulates ERK signaling, and furthermore that this can be abolished by trametinib. We finally generated cisplatin-resistant NPC models and demonstrated that trametinib was effective in inhibiting cisplatin-resistant NPC growth, colony formation and survival via suppressing ERK signaling in vitro and in vivo. Our work demonstrates the potential of trametinib in overcoming chemoresistance in preclinical NPC models and provides evidence of initializing clinical trials of using trametinib for NPC treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pancreatic cancer is one of the most aggressive cancers with a poor prognosis and 5-year low survival rate. In the present study, we report that bruceine A, a quassinoid found in Brucea javanica (L.) Merr. has a strong antitumor activity against human pancreatic cancer cells both in vitro and in vivo. Human proteome microarray reveals that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is the candidate target of bruceine A and both fluorescence measurement and microscale thermophoresis suggest bruceine A binds to PFKFB4. Bruceine A suppresses glycolysis by inhibiting PFKFB4, leading to cell cycle arrest and apoptosis in MIA PaCa-2 cells. Furthermore, glycogen synthase kinase-3 β (GSK3β) is identified as a downstream target of PFKFB4 and an PFKFB4-interacting protein. Moreover, bruceine A induces cell growth inhibition and apoptosis through GSK3β, which is dysregulated in pancreatic cancer and closely related to the prognosis. In all, these findings suggest that bruceine A inhibits human pancreatic cancer cell growth via PFKFB4/GSK3β-mediated glycolysis, and it may serve as a potent agent for curing human pancreatic cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Supramolecular drug self-delivery systems (SDSDSs) involving active drugs as building blocks linked by supramolecular interactions have been well defined as an advanced chemotherapy strategy. However, the lack of detecting release of drugs from SDSDSs at specific tumor sites inevitably leads to unsatisfactory therapeutic effects, owing to the lack of information regarding the administration of these drugs. In this work, predesigned platinum-containing supramolecular drug self-delivery nanomicelles ( SDSDNM s) were employed to synchronously realize drug monitoring by computed tomography imaging, immediately reflecting the evolution of drug release and real-time treatment at the tumor site. The appropriate administration dosage (1.2 mg mL -1 ,100 μL) and the injection interval (once every 3 days) needed to guide the antitumor activity of SDSDNM s were then defined, thereby attaining the aim of efficient synergistic combination chemotherapy. In vivo tumor inhibition and histological analyses showed that SDSDNM s exhibited a strong tumor inhibition effect and good safety with respect to normal organs. Such a supramolecular drug self-delivery strategy with monitored functions may offer new potential opportunities for application in the field of synergistic combination chemotherapy.

The heat shock protein 90 inhibitor, luminespib, has demonstrated potent preclinical activity against numerous cancers. However, clinical translation has been impeded by dose-limiting toxicities that have necessitated dosing schedules which have reduced therapeutic efficacy. As such, luminespib is a prime candidate for reformulation using advanced drug delivery strategies that improve tumor delivery efficiency and limit off-target side effects. Specifically, thermosensitive liposomes are proposed as a drug delivery strategy capable of delivering high concentrations of drug to the tumor in combination with other chemotherapeutic molecules. Indeed, this work establishes that luminespib exhibits synergistic activity in lung cancer in combination with standard of care drugs such as cisplatin and vinorelbine. While our research team has previously developed thermosensitive liposomes containing cisplatin or vinorelbine, this work presents the first liposomal formulation of luminespib. The physico-chemical properties and heat-triggered release of the formulation were characterized. Cytotoxicity assays were used to determine the optimal drug ratios for treatment of luminespib in combination with cisplatin or vinorelbine in non-small cell lung cancer cells. The formulation and drug combination work presented in this paper offer the potential for resuscitation of the clinical prospects of a promising anticancer agent.

Ethnopharmacological Relevance: Poria cocos Wolf has been used in traditional East-Asian medicine for centuries to effectively treat various gastrointestinal disorders such as diarrhea for its tonic, anti-fungal and anti-bacterial activities. Previous studies have revealed that the tumor development would induce intestinal microbiota dysbiosis and intestinal barrier dysfunction to the patients with breast cancer., Aim of Study: To investigate the effect and the mechanism of ethanol extract of Poria cocos (PC) on intestinal barrier function and intestinal microbiota in the mice with breast cancer., Materials and Methods: Thirty-six female BALB/c mice were randomly divided into four groups (the normal control, model, PC and positive control group). Intestinal histopathological was evaluated by H&E staining. The difference of the intestinal microbiota in each group was studied by 16S rDNA high-throughput sequencing. The level of plasma endotoxin, D -lactic acid (D-LA) and diamine oxidase (DAO) were measured by ELISA. The putrescine content in serum and urine were detected by HPLC. Expression of the tight junction (TJ) proteins, phosphorylated p38 MAPK and ERK1/2 were determined by western blotting., Results: Our results showed that tumor development prominently induced the intestinal damage and microbiome dysbiosis in mice. PC prominently remit such histologic damage through enhancing the expression of TJ proteins and decreasing the levels of DAO, D-LA and endotoxin via upregulating the expression of phosphorylated ERK1/2 and p38 MAPK. Furthermore, PC increased the diversity of the intestinal microbiota and strikingly changed the structure and composition of the gut microbiota in the mice by increasing the beneficial bacteria Lactobacillus, Bifidobacterium, and decreasing the sulfate-reducing bacteria Desulfovibrio and inflammatory associated bacteria Mucispirillum, S24-7 and Staphylococcus. Moreover, PICRUSt analysis and the putrescine detection might indicate that PC might be involved in the putrescine metabolism in the mice. Correlation analysis indicated that Prevotella, Rikenellaceae and Bacteroidetes were significantly correlated with Claudin-8 and p38-MAPK expression (p < 0.05)., Conclusion: PC could improve the dysbacteriosis and repair the intestinal barrier function in the mice with breast cancer. This study provide more data to support the application of PC in breast cancer treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

PI3Kδ (phosphatidylinositol 3-kinase-δ), one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ for patients with indolent non-Hodgkin lymphomas. Here in this paper, we comprehensively evaluated the in vitro and in vivo antitumor activity of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary chronic lymphocytic leukemia (CLL) cells. Scid mice were subcutaneously inoculated with the SU-DHL-6 cell line. SHC014748M was more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells. SHC014748M also inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in both lymphoma cells and primary CLL cells. In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 in patient serum decreased sharply after SHC014748M treatment. According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Paraneoplastic pemphigus (PNP) is a severe autoimmune syndrome commonly triggered by neoplasms. The prognosis of CLL-associated PNP is dismal due to its refractory course and secondary infection and no standard treatment was recommended. We retrospectively reported six CLL with PNP cases from 842 cases of CLL including diagnosis, treatment and prognosis. The median time between the initial of CLL to PNP was 36 months while the median overall survival from the diagnosis of PNP was 26 months. And three cases died of lung infection while 5 developed pulmonary symptoms. And 5 cases received fludarabine-based chemotherapy before developing PNP, which suggesting fludarabine was one of potential causes of PNP. For the treatment, five patients were rescued by combined regimens including rituximab, methylprednisolone, immunoglobulin, fresh frozen plasma and the last received ibrutinib combined with short-term prednisone. Fludarabine-based regimen may be one of the potential causes of PNP. The combined regimen might shed a new light, while ibrutinib is a promising drug for CLL with PNP, but needs much more evidence. PNP should be carefully treated to guide early diagnosis and intervention for a better prognosis.

Gastric cancer is one of the most common malignant tumors in the world. In China, its morbidity and mortality are second only to lung cancer. Chemotherapy combined with targeted therapy brings survival benefits to patients with advanced gastric cancer. Targets for targeted therapy of gastric cancer include human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR) and Claudin 18.2 (CLDN 18.2). The main challenge of tumor molecule-targeted drugs is resistance. The main mechanisms of drug resistance include tumor establishment of compensatory signaling pathways, target protein changes, tumor microenvironment changes, tumor heterogeneity and tumor adaptation to targeted drugs. The combined action of multiple drug resistance mechanisms promotes the development of targeted drug resistance. In order to attract the attention of researchers, this paper reviews the mechanisms of drug resistance in gastric cancer-targeted therapy. In addition, the research status of drug resistance in molecule-targeted therapy of gastric cancer is summarized. It is of great clinical significance to explore the drug resistance mechanisms of targeted drugs and reverse drug resistance in gastric cancer. Last, the future development of molecule-targeted therapy is prospected., (Copyright 2020 Clarivate Analytics.)

In an effort to enhance antitumor and anti-metastasis of breast cancer, honokiol (HNK) was encapsulated into hyaluronic acid (HA) modified cationic liposomes (Lip). The prepared HA-Lip-HNK had a spherical shape with a narrow size distribution. The enhanced antitumor efficacy of HA-Lip-HNK was investigated in 4T1 cells in vitro, wherein flow cytometry and confocal microscopy analysis revealed its HA/CD44-mediated greater cellular internalization. As anticipate, the significant cytotoxicity of the HA-Lip-HNK was also observed in 4T1 tumor spheroids. Furthermore, the superior prevention of tumor metastasis by HA-Lip-HNK was verified by in vitro anti-invasion, wound healing and anti-migration assessments, and in vivo bioluminescence imaging in pulmonary metastasis model. Finally, compared with unmodified liposomes, the HA-Lip-HNK exhibited higher tumor accumulation, and achieved a tumor growth inhibition rate of 59.5 %. As a result, the HA-Lip-HNK may serve as a promising tumor-targeted drug delivery strategy for the efficient therapy of metastatic breast cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Fibroblast growth factor receptor 1 (FGFR1) is one of the attractive pharmaceutical targets for cancer therapy. The FGFR1 targeting antagonist peptides, especially of the short peptides harbouring only coding amino acid might highlights promising aspects for their higher affinity, specificity and lower adverse reactions. However, most of peptides inhibitors remain in preclinical research, likely associating with their instability and short half-life. In this study, we found a stable short peptide inhibitor P48 and speculated that its stability might be related to its non-linear spatial structure. In addition, P48 could target the extracellular immunoglobulin domain of FGFR1, and effectively block the particular signaling pathways of FGFR1, which lead to the inhibition of cancer proliferation, invasion in vitro and restraint of tumor growth in vivo. Together, this study provided a promising FGFR1 inhibitor with the potential to be developed as an antitumor drug., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Coumarin-based anti-cancer agents have attracted considerable attention recently. Butyrate, a major short-chain fatty acid produced in colon by gut microbiota, has been shown to exert anticancer activity both in vitro and in vivo. In this study, we evaluated the anti-cancer effect of combining glycyrol (GC), a representative of coumarin compounds in licorice, or its analogues Glycycoumarin/Demethylsuberosin/Coumestrol (GCM/De/Coum) with butyrate in HT29 and HCT116 cells, and explored the relationship between the combined anti-cancer effect and structural features of coumarin compounds. Results showed the strongest inhibitory effect on cancer cells was induced by GC/butyrate combination via enhanced activation of caspase-3. Our data indicated the benzofuranyl, isopentenyl and methoxy groups presented in GC played critical role in its anti-cancer activity, while the furan group led to the further enhancement. The findings of the present study will be beneficial for developing coumarin-based compounds and coumarin compound-based regimen to fight against colon cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Histone deacetylase 3 (HDAC3) has been suggested to play a role in hepatocellular carcinoma (HCC). In the present report, we aimed to identify the effects of RGFP966, a specific HDAC3 inhibitor, on the cell proliferation and migration of HCC cell lines., Methods: Human HCC cell lines, which were identified using short tandem repeat (STR) DNA profiling analysis, were used in this report. Cell proliferation assay was used to identify the growth viability of cells. Wound healing and transwell assay were used to identify the migration ability of cells. Further, a human phospho-receptor tyrosine kinases array kit was used to screen out RGFP966 effects on key receptor tyrosine kinases. Then, the mRNA expression was quantified by real-time PCR, and protein expression was identified by Western blot immunoassay., Results: We found that RGFP966 inhibited both proliferation and migration of HCC cells. Further, RGFP966 represses the expression and phosphorylation levels of epidermal growth factor receptor (EGFR) in HCC cells. Moreover, HDAC3 is involved in the inhibition of EGFR by RGFP966. Overall, we elucidated an inhibitive function of RGFP966 in HCC progression., Conclusion: RGFP966 inhibits EGFR signaling pathway and suppresses proliferation and migration of HCC cells., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Yu et al.)

Cancer, which has been cursed for human beings for long time is considered as one of the leading causes of morbidity and mortality across the world. In spite of different types of treatments available, chemotherapy is still deemed as a favored treatment for the cancer. Unfortunately, many currently accessible anticancer agents have developed multidrug resistance along with fatal adverse effects. Therefore, intensive efforts have been made to seek for new active drugs with improved anticancer efficacy and reduced adverse effects. In recent years, the emergence of heterocyclic ring-containing anticancer agents has gained a great deal of attention among medicinal chemists. 1,3- oxazole is a versatile heterocyclic compound, and its derivatives possess broad-spectrum pharmacological properties, including anticancer activity against both drug-susceptible, drug-resistant and even multidrug-resistant cancer cell lines through multiple mechanisms. Thus, the 1,3-oxazole moiety is a useful template for the development of novel anticancer agents. This review will provide a comprehensive overview of the recent advances on 1,3-oxazole derivatives with potential therapeutic applications as anticancer agents, focus on the chemical structures, anticancer activity, and mechanisms of action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Gastric Cancer (GC) is one of the most malignant and lethal tumors worldwide. The hypoxic microenvironment is correlated with GC cell invasion, metastasis and Epithelial-Mesenchymal Transition (EMT). Resveratrol is a compound extracted from various plants, including grapes, berries, and some traditional Chinese medicines. Recently, the anticancer properties of resveratrol against many cancers have been reported in a range of studies. However, the exact mechanism through which resveratrol prevents GC invasion and metastasis under hypoxic conditions remains unclear., Objective: The objective of this study is to show to what extent resveratrol could inhibit the hypoxia-induced malignant biological behavior of GC., Methods: SGC-7901 cells were cultured in a consistent 3% O2 hypoxic condition or 21% O2 normal condition for 48 hours to establish an in vitro hypoxia model. Western blot and qRT-PCR were used to detect EMT markers of SGC- 7901 cells, including E-cadherin, HIF-1a, Vimentin, etc. Transwell Matrigel Invasion Assays were used to test the invasive ability of SGC-7901 cells. The siRNA targeting Gli-1 showed its role in hypoxia-induced EMT and invasion of SGC-7901 cells., Results: Resveratrol was found to significantly decrease HIF-1α protein levels induced by hypoxia in SGC-7901 cells. HIF-1α accumulation was found to promote cell proliferation, migration, and invasive capacities in addition to EMT changes through the activation of the Hedgehog pathway. These effects were found to be reversed by resveratrol., Conclusion: Therefore, these data indicate that resveratrol may serve as a potential anticancer agent for the treatment of GC, even in a hypoxic tumor microenvironment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gynecological cancers are the most commonly diagnosed forms of cancer among the female population. Chitooligosaccharides (COS)-hydrolysis products from chitosan-display high bioavailability, high water solubility, and low molecular weight properties. Here, we investigated the influence of COS on 11 gynecological tumor cell types, and subsequently elucidated molecular mechanisms through which the observed inhibition occurred. Initially, we used a controllable enzyme-membrane coupling reactor system to obtain COS with a high degree of polymerization; the yield of high-degree-polymerized COS (DP 5-12) obtained with this reactor system accounted for ∼75% yields (w/w). Using these COS materials, cell line assays showed that COS elicited the most significant anti-tumor activity against C33A cells, with anti-tumor mechanisms related to oxidative stress, as well as activation of intrinsic mitochondrial apoptosis and autophagic signaling. Thus, we provide experimental evidence to demonstrate how the enzyme-membrane coupling reactor system can generate COS that exert bioactivity against gynecological cancers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The anticancer therapies with the joint treatment of a histone deacetylase (HDAC) inhibitor and a DNA-damaging approach are actively under clinical investigations, but the underlying mechanism is unclear. Histone homeostasis is critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival. We have previously demonstrated that the HDAC inhibitor, trichostatin A (TSA), could promote the degradation of the core histones induced by γ-radiation or the DNAalkylating agent methyl methanesulfonate (MMS) in non-cancer cells, including mouse spermatocyte and embryonic fibroblast cell lines. In this study, we found that the joint treatment by TSA and MMS induced the death of the cultured cancer cells with an additive effect, but induced degradation of the core histones synergistically in these cells. We then analyzed various combinations of other HDAC inhibitors, including suberoylanilide hydroxamic acid and valproate sodium, with MMS or other DNAdamaging agents, including etoposide and camptothecin. Most of these combined treatments induced cell death additively, but all the tested combinations induced degradation of the core histones synergistically. Meanwhile, we showed that cell cycle arrest might not be a primary consequence for the joint treatment of TSA and MMS. Given that clinic treatments of cancers jointly with an HDAC inhibitor and a DNA-damaging approach often show synergistic effects, histone degradation might more accurately underlie the synergistic effects of these joint treatments in clinic applications than other parameters, such as cell death and cell cycle arrest. Thus, our studies might suggest that the degradation of the core histones can serve as a new target for the development of cancer therapies.

Background: Cytotoxin 1 (CTX1) purified from Naja atra Cantor venom could inhibit cancer cell proliferation, but the mechanism is not clear. This study aimed to investigate the mechanism by which leukemia cells are killed by CTX1., Materials and Methods: HL-60 and KG1a cells were treated with CTX1 and the cell death was detected., Results: The viability of HL-60 and KG1a cells decreased in a dose- and time-dependent manner after treatment with CTX1. CTX1 mainly induced late apoptosis and necrosis. The cell death induced by CTX1 could be rescued by specific necroptosis inhibitor Nec-1 but not by caspase inhibitor Z-VAD-fmk in HL-60 cells. In addition, CTX1 increased lysosome membrane permeability (LMP) and release of cathepsin B., Conclusion: CTX1 could induce necroptosis in leukemia cells, and it is related to LMP increase and cathepsin release. CTX1 could be a promising anti-cancer drug for leukemia therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The overall incidence of cancer is increasing in recent years. Despite advances in various comprehensive treatments, the mortality of advanced malignant tumors remains at a high level. Numerous pharmacological studies have confirmed that many Chinese herbal medicines possess remarkable antitumor activities. Amygdalin, mainly existing in bitter almond, is reported to have antitumor properties in addition to the antioxidative, antibacterial, anti-inflammatory and immunoregulatory activities. This article summarizes the structural characteristics of amygdalin, its antitumor mechanisms, and recent progress and achievement in the research of amygdalin, hoping that it could provide theoretical clues for exploring the clinical value of amygdalin against tumors. Amygdalin is known to have an antitumor effect in solid tumors such as lung cancer, bladder cancer and renal cell carcinoma by affecting cell cycle, inducing apoptosis and cytotoxicity, and regulating immune function. Further research is needed to elucidate the pharmacological mechanisms of amygdalin in terms of the optimal dosage, the feasibility of combined use of amygdalin with other antitumor drugs, and even artificial synthesis of the active components in amygdalin, for the sake of enhancing its antitumor activities and reducing its adverse effects for clinical use., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Cancer is still a major risk factor to public health globally, causing approximately 9.8 million deaths worldwide in 2018. Despite advances in conventional treatment modalities for cancer treatment, there are still few effective therapies available due to the lack of selectivity, adverse side effects, non-specific toxicities, and tumour recurrence. Therefore, there is an immediate need for essential alternative therapeutics, which can prove to be beneficial and safe against cancer. Various phytochemicals from natural sources have been found to exhibit beneficial medicinal properties against various human diseases. Zerumbone is one such compound isolated from Zingiber zerumbet Smith that possesses diverse pharmacological properties including those of antioxidant, antibacterial, antipyretic, anti-inflammatory, immunomodulatory, as well as anti-neoplastic. Zerumbone has shown its anti-cancer effects by causing significant suppression of proliferation, survival, angiogenesis, invasion, and metastasis through the molecular modulation of different pathways such as NF-κB, Akt, and IL-6/JAK2/STAT3 (interleukin-6/janus kinase-2/signal transducer and activator of transcription 3) and their downstream target proteins. The current review briefly summarizes the modes of action and therapeutic potential of zerumbone against various cancers.

Hyaluronic acid (HA)-modified amino single-walled carbon nanotubes (NH₂-SWCNTs) were developed for targeted delivery of doxorubicin (DOX) to improve breast cancer treatment. HA, which specifically binds to the CD44 receptor, was non-covalently coated on NH₂-SWCNTs through simply electrostatic adsorption. The formed SWCNTs-DOX-HA complexes were characterized in terms of morphology, particle size and zeta potential by different techniques. The DOX loading percentage on the SWCNTs-DOX-HA complexes was 81.5±1.0 %. In vitro release study showed that the release of DOX was pH-triggered and was faster at a lower pH 5.5 (tumor cell microenvironment) than that under physiological conditions (pH 7.4), which was beneficial for intracellular drug release. The SWCNTs-DOX-HA showed a significantly improved intracellular delivery of DOX in CD44 overexpressing MDA-MB-231 cells by flow cytometry and confocal microscopy. Of particular importance, the SWCNTs-DOX-HA complexes were better than the unmodified SWCNTs-DOX on inhibiting proliferation and inducing apoptosis of cells. In addition, the migration of MDA-MB-231 cells was significantly blocked by SWCNTs-DOX-HA. In the cancer cell spheroids assay, SWCNTs-DOX-HA exhibited notable effect to inhibit the growth of cancer cell spheroids. All these results indicated that this developed SWCNTs-DOX-HA complexes hold a great promise to be used as an efficient nano-sized anticancer drug formulation for tumor-targeted treatment.

Background: Cancer metastasis has emerged as a major public health threat that causes majority of cancer fatalities. Traditional chemotherapeutics have been effective in the past but suffer from low therapeutic efficiency and harmful side-effects. Recently, it has been reported ursolic acid (UA), one of the naturally abundant pentacyclic triterpenes, possesses a wide range of biological activities including anti-inflammatory, anti-atherosclerotic, and anti-cancer properties. More importantly, UA has the features of low toxicity, liver protection and the potential of anti-cancer metastasis., Objective: This article aimed at reviewing the great potential of UA used as a candidate drug in the field of cancer therapy relating to suppression of tumor initiation, progression and metastasis., Methods: Selective searches were conducted in Pubmed, Google Scholar and Web of Science using the keywords and subheadings from database inception to December 2017. Systemic reviews are summarized here., Results: UA has exhibited chemopreventive and therapeutic effects of cancer mainly through inducing apoptosis, inhibiting cell proliferation, preventing tumor angiogenesis and metastatic. UA nanoformulations could enhance the solubility and bioavailability of UA as well as exhibit better inhibitory effect on tumor growth and metastasis., Conclusion: The information presented in this article can provide useful references for further studies on making UA a promising anti-cancer drug, especially as a prophylactic metastatic agent for clinical applications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: To evaluate the efficacy and safety of abiraterone acetate (AA) plus prednisone compared with prednisone alone in Asian patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), and to identify predictive factors., Methods: We reviewed the medical records of 60 patients with chemotherapy-naive mCRPC at Renji Hospital who were treated with AA plus prednisone (n = 43) or prednisone alone (n = 17). All patients were assessed for prostate-specific antigen (PSA) response, PSA progression-free survival (PSA PFS), radiographic progression-free survival (rPFS), and overall survival (OS). The ability of several parameters to predict PSA PFS, rPFS, and OS was studied., Results: The median follow-up time was 14.0 months (range 7.0-18.5 months), at which time 19 death events had been reported: 11 in the AA + prednisone group and 8 in the prednisone group. The AA + prednisone group had significantly longer median PSA PFS (10.3 vs 3.0 months, P < 0.001), rPFS (13.9 vs 3.9 months, P < 0.001), and OS (23.3 vs 17.5 months, P = 0.016) than the prednisone-alone group. The most frequently reported grade 3 or 4 adverse event in both the AA + prednisone and prednisone-alone groups was elevated alanine aminotransferase level in 5 of 43 patients (11.6%) and 2 of 17 patients (11.8%), respectively. No adverse events led to discontinuation of therapy. In multivariate analysis, time from androgen deprivation therapy (ADT) to castration resistance of ≤18 months was a determinant of shorter OS (P = 0.007)., Conclusions: These results support the favourable safety and efficacy profile of AA for the treatment of Asian patients with chemotherapy-naive mCRPC. Longer duration of ADT response was significantly associated with longer survival.

Ursolic acid (UA), a natural triterpene acid, is a promising anti-cancer drug due to its inhibitory effect on tumor growth and metastasis. However, clinical translation of UA is limited by its poor water solubility and low bioavailability. To overcome these problems, herein an amphiphilic self-assembly nanodrug composed of UA, lactobionic acid (LA) and low-polyamidoamine (low-PAMAM) dendrimers is developed. This near-spherical nanodrug with a uniform size (~180 nm) demonstrated to have an enhanced cytotoxicity against liver cancer SMMC7721 cells, and could attenuate the migration and adhesion of SMMC7721 cells at non-toxic concentrations by suppressing metastasis-related protein MMP-9 expression. Furthermore, in vivo study indicates that the nanodrug exhibited prolonged circulation time in blood as well as increased AUC, MRT and C max , and could effectively inhibit the tumor growth in H22 mice model. Overall, the UA-based nanodrug delivery system reported in the present work represents a novel strategy for targeted tumor therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Ovarian cancer is one of the deadliest gynecological malignancies in women. Chemoresistance has been a major obstacle for ovarian cancer treatment. Zinc finger E-box-binding homeobox 1 (ZEB1) is an important regulator of tumor development in various types of cancer. Abnormal expression of SLC3A2 (CD98hc), a type 2 transmembrane cell surface molecule, has been described in several cancers. This study was designed to investigate the role of ZEB1 and SLC3A2 in the chemoresistance to cisplatin in ovarian cancer cells. We found that ZEB1 was increased in cisplatin-resistant SKOV3/DPP cells. Downregulation of ZEB1 significantly decreased cell viability in response to cisplatin, increased cis-platin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. In addition, downregulation of ZEB1 decreased the volume and weight of implanted tumors. SLC3A2 was decreased in cisplatin-resistant SKOV3/DPP cells. Upregulation of SLC3A2 significantly decreased cell viability in response to cisplatin, increased cisplatin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. Moreover, upregulation of SLC3A2 decreased the volume and weight of implanted tumors. Downregulation of ZEB1 resulted in a significant increase of SLC3A2 expression. Moreover, downregulation of SLC3A2 significantly inhibited ZEB1 knockdown-mediated inhibition of cisplatin-resistance. ZEB1-mediated regulation of SLC3A2 was involved in the chemoresistance to cisplatin in ovarian cancer cells. Overall, we provide new insights into the mechanism of chemoresistance to cisplatin in ovarian cancer cells. ZEB1/SLC3A2 may be promising therapeutic targets for enhancement of the sensitivity of ovarian cancer cells to cisplatin-mediated chemotherapy., (© 2018 S. Karger AG, Basel.)

Co-delivery multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a pH sensitive mesoporous silica nanoparticles (MSN) based controlled release nanoparticles for co-delivery of sorafenib (SO), a multi-tyrosine kinase inhibitor, and ursolic acid (UA), a sensitive agent for SO, was developed, which was decorated with pH sensitive chitosan (CS) and lactobionic acid (LA) targeting to asialoglycoprotein receptor (ASGPR) over-expressing hepatocellar carcinoma cells (denoted as USMNs-CL). The nanocomplex enhanced bioavailability of hydrophobic drugs, efficient tumor cell targeting and exhibited pH-responsive function and sustained release profile. USMNs-CL showed synergistic cytotoxicity and could attenuate the adhesion, migration of ASGPR over-expressing liver cancer SMMC-7721 cells at non-toxic concentrations. Moreover, the complex nanoparticles significantly increased the cellular apoptosis and down-regulated the expression of EGFR and VEGFR2 proteins related with cell proliferation and tumor angiogenesis. In vivo, compared with UA or SO alone, the nanocomplex significantly reduced the tumor burden in hepatocellular carcinoma (HCC) H22 tumor-bearing mice model and inhibited the lung metastasis in the H22 lung metastasis models. Overall, co-delivery of UA and SO by MSN-CS-LA nanocarriers could provide a promising strategy for HCC combinational therapy, especially for the HCC metastasis chemoprevention., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To determine if prognostic nutritional index (PNI) and its variation could predict initial response to treatment and prognosis in metastatic castration-resistant prostate cancer (mCRPC) patients treated with Abiraterone (AA)., Patients and Methods: One-hundred-twelve chemotherapy pretreated or chemotherapy-naive patients were scheduled for systemic treatment with AA. PNI levels were measured before and after one month of AA treatment. Univariate and multivariate logistic regression analyses were used to identify predictive factors of initial response to AA treatment. Univariable and Multivariable Cox regression analyses were performed to determine prognostic factors that were associated with PSA progression-free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). The Harrell concordance index with variables only or combined PNI data were used to evaluate the prognostic accuracy., Results: Eighty-one (72.3%) of 112 patients showed initial response to AA treatment, in which 15 experienced PSA flare during AA treatment. In multivariate logistic regression analyses, high baseline PNI level, PSA level decrease during the first month of AA treatment and PNI level elevation during the first month of AA treatment were significantly correlated with initial response to AA treatment. In multivariate Cox regression analysis, low PNI level remained significant predictors of OS, rPFS and PSA-PFS. The estimated c-index of the multivariate model for OS increased from 0.82 without PNI to 0.83 when PNI added., Conclusion: Independent of PSA level variation, PNI level elevation during the first month of AA treatment and high baseline PNI level were significantly correlated with initial response to AA treatment. In addition, low pretreatment PNI level is a negative independent prognosticator of survival outcomes in mCRPC treated with AA and also increases the accuracy of established prognostic model., (© 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.)

Objective: To determine the prognostic utility of serum chromogranin A (CgA) and neurone-specific enolase (NSE) variations during the first 3 months of abiraterone acetate (AA) treatment in patients with metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: The serum levels of CgA, NSE were measured at baseline and after 3 months of AA treatment in 40 patients with mCRPC. Outcome measures were prostate-specific antigen progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS)., Results: CgA levels were not correlated with NSE levels (P = 0.296). In multivariate analysis the combination of CgA and NSE (≥1 marker positive vs both markers negative) and the combination of CgA and NSE elevation during the first 3 months of AA treatment (≥1 marker positive vs both markers negative) remained significant predictors of OS, rPFS, and PSA-PFS., Conclusion: We found that CgA and NSE elevation during the first 3 months of AA treatment and elevated baseline CgA and NSE levels were independent prognostic factors for OS, rPFS and PSA-PFS in patients with mCRPC treated with AA. This suggests that serial CgA and NSE evaluation may help clinicians in distinguishing patients with mCRPC who would obtain the best survival benefit from AA treatment., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells. We also found that inhibition or depletion of BET proteins impairs transcription of BRCA1 and RAD51 , two genes essential for HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal models of HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene was focally amplified across 20 types of common cancers. Combination with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

In this study, we investigated anti-tumor activity and associated molecular mechanism of action of Salicylate ●Phenanthroline Copper (II) Complex in triple-negative breast cancer. Salicylate ●Phenanthroline Copper (II) Complex inhibited the growth of four breast cancer cell lines (MCF-7, T47D, MDA-MB-231 and BT-20) and induced apoptosis in a concentration-dependent manner. The effect was more profound in MDA-MB-231 and BT-20 triple-negative breast cancer cell lines. Western blot showed that the expression of the apoptosis-related protein Bcl-2, Bcl-xl and survivin was significantly reduced in MDA-MB-231 after treatment with Salicylate ●Phenanthroline Copper (II) Complex. In vivo, Salicylate ●Phenanthroline Copper (II) Complex administration significantly attenuated tumor growth of MDA-MB-231 xenografts, and the expression levels of Bcl-2, Bcl-xL and survivin were reduced as measured by immunohistochemical staining. These data suggest that Salicylate ●Phenanthroline Copper (II) Complex is a promising novel therapeutic drug for triple-negative breast cancer and warrants further study.

Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objective: To evaluate the cost-effectiveness of second-line nilotinib vs dasatinib among patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) who are resistant or intolerant to imatinib, from a US third-party perspective., Methods: A lifetime partitioned survival model was developed to compare the costs and effectiveness of nilotinib vs dasatinib, which included four health states: CP on treatment, CP post-discontinuation, progressive disease (accelerated phase [AP] or blast crisis [BC]), and death. Time on treatment, progression-free survival, and overall survival of nilotinib and dasatinib were estimated using real-world comparative effectiveness data. Parametric survival models were used to extrapolate outcomes beyond the study period. Drug treatment costs, medical costs, and adverse event costs were obtained from the literature and publicly available databases. Utilities of health states were derived from the literature. Incremental cost-effectiveness ratios, including incremental cost per life-year (LY) gained and incremental cost per quality-adjusted life-year (QALY) gained, were estimated comparing nilotinib and dasatinib. Deterministic sensitivity analyses were performed by varying patient characteristics, cost, and utility inputs., Results: Over a lifetime horizon, nilotinib-treated patients were associated with 11.7 LYs, 9.1 QALYs, and a total cost of $1,409,466, while dasatinib-treated patients were associated with 9.5 LYs, 7.3 QALYs, and a total cost of $1,422,122. In comparison with dasatinib, nilotinib was associated with better health outcomes (by 2.2 LYs and 1.9 QALYs) and lower total costs (by $12,655). Deterministic sensitivity analysis results showed consistent findings in most scenarios., Limitations: In the absence of long-term real-world data, the lifetime projection could not be validated., Conclusions: Compared with dasatinib, second-line nilotinib was associated with better life expectancy, better quality-of-life, and lower costs among patients with Ph+ CML-CP who were resistant or intolerant to imatinib.

Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been demonstrated to exhibit good anti-cancer effect. In this study, a series of novel quaternary ammonium salts of emodin, anthraquinone and anthrone were synthesized and their anticancer activities were tested in vitro. The effects of emodin quaternary ammonium salts on cell viability, apoptosis, intracellular ROS, and mitochondrial membrane potential were investigated in A375, BGC-823, HepG2 and HELF cells. The results demonstrated that compound 4a induced morphological changes and decreased cell viability. Apoptosis triggered by compound 4a was visualized using DAPI staining and Annexin V-FITC/PI staining. Compound 4a-induced apoptosis of A375 cells were showed to be associated with the dissipation of mitochondrial membrane potential (ΔΨm) as a result of the up-regulation of P53 and Caspase-3. When cancer cells were treated with emodin derivative, their ability to generate reactive oxygen species (ROS) rose significantly and the mitochondrial membrane potential decreased. Additionally, confocal microscopy assay confirmed that compound 4a was primarily located in the mitochondria of A375 cells. These results suggested that compound 4a has the potential for use in cancer therapy., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Ursolic acid (UA) as a nature product exhibits good anti-cancer activity, low toxicity, and good liver protection features. However, the low-solubility and poor bioavailability restrict its further clinical application. To overcome this problem, a pH-sensitive prodrug delivery system (UA@MSN-UA) that incorporated acid-sensitive linkage between drug and silica-based mesoporous nanosphere (MSN) was successfully designed and synthesized. The physicochemical properties of the UA@MSN-UA nanoparticles were investigated for shape, particle size, zeta potential, nitrogen adsorption-desorption and infrared (IR) spectroscopy. The nanoparticles were further evaluated for in vitro cytotoxicity, including proliferation inhibition, cell cycle distribution and apoptotic effects against human hepatocellular carcinoma HepG2 cells. The TEM image showed that the size of synthesized MSN nanoparticle was a near-spherical shape with ~100nm diameter. In vitro cytotoxicity testing demonstrated that UA@MSN-UA nanoparticles prodrug exhibited higher proliferation inhibition, cell cycle arrest at the G2/M phase and significantly caused the early and late apoptosis in HepG2 cells, which would be contributed to high loading capacity, high cellular uptake and sustained release of UA. Overall, the UA-modified MSN prodrug delivery system can be a promising drug carrier for improving the bioavailability of UA, and further enhance its anti-cancer efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)