Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 19, 2023

Background: Pancreatic cancer (PC) is a type of cancer with a high incidence and case-fatality rate.Objective: This study aimed to evaluate the role of statins in preventing mortality following PC based on scientific evidence with systematic review and meta-analysis method.Methods: This meta-analysis considered studies published from 1980 till the end of 2022 in ISI Web of Science, Scopus, PubMed, Cochrane, Science Direct, Google Scholar, and Embase databases. Funnel diagrams and Begg's and Egger's tests were used to assess the publication bias.Results: In general, this meta-analysis has included 19 studies (13 cohort studies, 4 case-control, and 2 randomized clinical trials (RCTs)) and a total of 100,888 patients with PC. The risk of mortality of PC in statin users in total was 0.86 (95% CI: 0.80 - 0.92, P-value <0.001); in the case-control studies, it was equal to 0.53 (0.34-0.83); in the cohort studies, it was equal to 0.87 (0.82-0.92, P-value <0.001); in RCTs, it was equal to 1.19 (0.99-1.42, P-value <0.001); in studies with good quality score category, it was equal to 0.92 (0.86-0.99, P-value <0.001), and in articles of the moderate quality score category, it was equal to 0.73 (0.64-0.84, P-value <0.001). The results of statistical tests indicated the existence of publication bias (Begg's test (P-value = 0.002) and Egger's test (P-value = 0.004)).Conclusion: Statins reduce the risk of mortality in patients with PC. However, no significant relation has been observed in RCTs. Therefore, it is necessary to be cautious in interpreting the results.

Background: Bevacizumab increased hypoxia-inducible factor (HIF-1α) expression attenuates its antitumor effect. Simvastatin can reduce the expression of HIF-1α to exert a tumor-suppressive effect in many in vitro experiments. Therefore, this study aimed to determine whether simvastatin could strengthen the anti-tumor activity of bevacizumab in lung adenocarcinoma. Objective: To determine whether simvastatin could strengthen the anti-tumor activity of bevacizumab in lung adenocarcinoma. Methods: The changes in the biological behavior of A549 cells treated with different drugs were determined through colony forming assay, Cell Counting Assay-8 (CCK-8), transwell assay, wound healing assay, and flow cytometry. The expressions of pathway-related factors HIF-1α and β-Catenin were determined via qRT-PCR and western blotting. The expressions of proliferation-related proteins, invasion-related proteins, and apoptosis-related proteins were detected by western blotting. In addition, a xenograft non-small cell lung cancer model in nude mice was used to explore in vivo tumor growth. Results: We found that simvastatin combined with bevacizumab synergistically suppressed the proliferation, migration, and invasion of A549 cells while promoting their apoptosis. As demonstrated by qRT-PCR and western blotting experiments, the bevacizumab group displayed a higher expression of pathway-related factors HIF-1α and β-Catenin than the control groups, however simvastatin group showed the opposite trend. Its combination with bevacizumab induced elevation of HIF-1α and β-catenin expressions. During in vivo experiments, simvastatin inhibited tumor growth, and in comparison, the inhibitory effects of its combination with bevacizumab were stronger. Conclusion: Based on our findings, simvastatin may affect the biological responses of bevacizumab on A549 cells by restraining the HIF-1α-Wnt/β-catenin signaling pathway, thus representing a novel and effective combination therapy that can be potentially applied in a clinical therapy for lung adenocarcinoma.

Background: Treatment options for advanced non-small-cell lung cancer (NSCLC) after osimertinib failure are limited, and osimertinib continuation is recommended for selected patients. Metronomic oral vinorelbine is an effective treatment with less toxicity for advanced NSCLC.Objective: The objective of the study was to investigate the effects of osimertinib plus metronomic oral vinorelbine on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC beyond limited progression on osimertinib.Methods: We have reviewed the medical records of 28 patients with EGFR-mutant advanced NSCLC who had received osimertinib continuation plus metronomic oral vinorelbine beyond limited progression on osimertinib. We also evaluated the clinicopathological characteristics of enrolled patients, as well as the efficacy and toxicity of the treatment.Results: After a median follow-up period of 14.1 months, 57.1% (16/28) of cases showed NSCLC progression. The median progression-free survival (PFS) period under osimertinib plus metronomic oral vinorelbine was 9.4 months (95% confidence interval, 1.562128;“17.238 months), with a disease control rate of 89.3% and objective response rate of 17.9%. PFS did not differ between patients who had previously received osimertinib as first- (n = 16) and second-line (n = 12) therapy (median, 11.4 and 4.7 months, P = 0.391). In addition, the median PFS duration did not differ according to the efficacy (PFS2 137;¥ 6 months vs. <6 months) of previous osimertinib monotherapy (median, 5.8 and 9.4 months, P = 0.677).Conclusions: Osimertinib continuation in conjunction with metronomic oral vinorelbine may enable overcoming TKI resistance and prolong the survival of patients with EGFR-mutant advanced NSCLC beyond limited progression on osimertinib treatment.

Background: Gastric cancer is one of the most common and deadliest malignancies in the world. Therefore, there is an urgent need to develop new and effective agents to reduce mortality. The plants of genus Inula have gained the attention of researchers worldwide as a rich source of potent medicinal compounds.Objective: This study explores the anti-cancer activity of Britannin, a sesquiterpene lactone isolated from Inula aucheriana DC., and its molecular mechanism in gastric cancer cells, AGS and MKN45.Methods: Cytotoxicity was evaluated through the MTT assay following 24 h, 48 h, and 72 h treatment with different concentrations of Britannin. Apoptosis rate and caspase-3 activity were measured 24 h after treatment by Britannin. . Western blotting was performed to determine the expression of the NF-ΚB, IΚBα, and PPARγ proteins. Moreover, quantitative RT-PCR was applied to measure the expression of NF-ΚB target genes.Results: We showed that Britannin induced cell growth inhibition and apoptosis in gastric cancer cells. Britannin caused an elevation in mRNA and protein levels of PPARγ. The involvement of PPARγ was more confirmed using GW9662, a PPARγ inhibitor. Suppression of NF-ΚB was demonstrated by western blot analysis. Down-regulation of MMP-9, TWIST-1, COX-2, and Bcl-2 and up-regulation of Bax were also observed in gastric cancer cells.Conclusion: These results imply that activation of the PPARγ signaling pathway through suppression of NF-ΚB underlies the anti-cancer properties of Britannin in gastric cancer. Therefore, Britannin could be considered as a promising anti-cancer candidate for further evaluation.

Background: Thyroid carcinoma (THCA) is one of the most prevalent endocrine tumors, accounting for 3.4% of all cancers diagnosed annually. Single Nucleotide Polymorphisms (SNPs) are the most prevalent genetic variation associated with thyroid cancer. Understanding thyroid cancer genetics will enhance diagnosis, prognosis, and treatment.Methods: This TCGA-based study analyzes thyroid cancer-associated highly mutated genes through highly robust in silico techniques. Pathway, gene expression, and survival studies were performed on the top 10 highly mutated genes (BRAF, NRAS, TG, TTN, HRAS, MUC16, ZFHX3, CSMD2, EIFIAX, SPTA1). Novel natural compounds from Achyranthes aspera Linn were discovered to target two highly mutated genes. The natural compounds and synthetic drugs used to treat thyroid cancer were subjected to comparative molecular docking against BRAF and NRAS targets. The ADME characteristics of Achyranthes aspera Linn compounds were also investigated.Results: The gene expression analysis revealed that the expression of ZFHX3, MCU16, EIF1AX, HRAS, and NRAS was up-regulated in tumor cells while BRAF, TTN, TG, CSMD2, and SPTA1 were down-regulated in tumor cells. In addition, the protein-protein interaction network demonstrated that HRAS, BRAF, NRAS, SPTA1, and TG proteins have strong interactions with each other as compared to other genes. The ADMET analysis shows that seven compounds have druglike properties. These compounds were further studied for molecular docking studies. The compounds MPHY012847, IMPHY005295, and IMPHY000939 show higher binding affinity with BRAF than pimasertib. In addition, IMPHY000939, IMPHY000303, IMPHY012847, and IMPHY005295 showed a better binding affinity with NRAS than Guanosine Triphosphate.Conclusion: The outcomes of docking experiments conducted on BRAF and NRAS provide insight into natural compounds with pharmacological characteristics. These findings indicate that natural compounds derived from plants as a more promising cancer treatment option. Thus, the results of docking investigations conducted on BRAF and NRAS substantiate the conclusions that the molecule possesses the most suited drug-like qualities. Compared to other compounds, natural compounds are superior, and they are also druggable. This demonstrates that natural plant compounds can be an excellent source of potential anti-cancer agents. The preclinical research will pave the road for a possible anti-cancer agent.

Background: Endometrial cancer is a very common and highly lethal reproductive malignant tumour in women. Paclitaxel (PTX) is a usual drug utilized in chemotherapy for endometrial cancer. It has been uncovered that PROM2 participates in the progression of various cancers through playing a promoter. However, the regulatory function of PROM2 in PTX treatment for endometrial cancer remains unclear.Methods: The cell viability (IC50) was examined through CCK8 assay. The mRNA and protein expressions of genes were measured through RT-qPCR and western blot. The proliferation was evaluated through colony formation and EdU assays. The cell apoptosis was assessed through flow cytometry.Results: In this work, through bioinformatic analysis on online websites, it is found that the up-regulated expression of PROM2 existed in endometrial cancer. In addition, the survival probability of UCEC patients with high PROM2 expression was worse. This study adopted PTX treatment for obtaining the PTX-resistant cells (HEC-1A/PTX and KLE/PTX). Furthermore, suppression of PROM2 enhanced PTX sensitivity through decreasing IC50 and proliferation in endometrial cancer. Additionally, knockdown of PROM2 facilitated cell apoptosis in HEC-1A/PTX and KLE/PTX cells. Next, we found that silencing of PROM2 retards the AKT/FOXO1 pathway. At last, rescue assays reversed the strengthened PTX sensitivity mediated by PROM2 inhibition after SC79 treatment (AKT activator).Conclusion: Knockdown of PROM2 enhanced PTX sensitivity in endometrial cancer through modulating the AKT/FOXO1 pathway. This study hinted that PROM2 may be a useful therapeutic target for PTX treatment in endometrial cancer.

Background: Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancerrelated deaths in women. Activation of EGFR by EC-secreted EGFR ligands promotes breast cancer progression. Current treatments provide limited benefits in triple-negative breast cancer (TNBC). Photodynamic therapy (PDT) has been proven effective for the treatment of TNBC through the EGFR pathway, but the underlying mechanism is still unclear.Purpose: The purpose of this study was to determine the role of the EGFR pathway in the treatment of PDT on TNBC in a co-culture system.Methods: MB-231 and HUVEC were co-cultured for experiments (HU-231). Cell viability and ROS production were detected after AE-PDT, a combination of EGFR inhibitors (AEE788)with PDT to test angiogenesis, apoptosis, and pyroptosis. WB detects expression of EGFR. EGFR, P-EGFR, VEGF, caspase-1, capase-3, and GSDMD .Results: AE-PDT inhibited HU-231 cell proliferation and tumor angiogenesis, and induced cell apoptosis and pyroptosis by promoting ROS production. AEE788, an inhibitor of the EGFR, enhanced HU-231 cell killing after AE-PDT.Conclusion: Our study suggested that the combination of EGFR inhibitors and AE-PDT could synergistically suppress breast cancer progression, providing a new treatment strategy.

Background: The new tetrandrine derivative is an anti-human liver cancer cell inhibitor which can be used to design and develop anti-human-liver-cancer drugs.Objective: A quantitative structure-activity relationship (QSAR) model was established to predict the physical properties of new tetrandrine derivatives using their chemical structures.Methods: The best descriptors were selected through CODESSA software to build a multiple linear regression model. Then, gene expression programming (GEP) was used to establish a nonlinear quantitative QSAR model with descriptors to predict the activity of a series of novel tetrandrine chemotherapy drugs. The best active compound 31 was subjected to molecular docking experiments through SYBYL software with a small fragment of the protein receptor (PDB ID:2J6M).Results: Four descriptors were selected to build a multiple linear regression model with correlation coefficients R2, R2CV and S2 with the values of 0.8352, 0.7806 and 0.0119, respectively. The training and test sets with a correlation coefficient of 0.85 and 0.83 were obtained via an automatic problem-solving program (APS) using the four selected operators as parameters, with a mean error of 1.49 and 1.08. Compound 31 had a good docking ability with an overall score of 5.8892, a collision rate of -2.8004 and an extreme value of 0.9836.Conclusion: The computer-constructed drug molecular model reveals the factors affecting the activity of human hepatocellular carcinoma cells, which provides directions and guidance for the development of highly effective anti-humanhepatocellular- carcinoma drugs in the future.

Introduction: The median survival of patients diagnosed with glioblastoma is very poor, despite efforts to improve the therapeutic effects of surgery, followed by treatment with temozolomide (TMZ) and ionizing radiation (IR). The utilization of TMZ or IR survivor cell models has enhanced the understanding of glioblastoma biology and the development of novel therapeutic strategies. In this present study, naïve U373 and clinically relevant U373 IRsurvivor (Surv) cells were used, as the IR-Surv cell model mimics the chronic long-term exposure to standardized radiotherapy for patients with glioblastoma in the clinic. As the role of ferroptosis in the IR survivor cell model has not previously been reported, we aimed to clarify its involvement in the clinically relevant IR-Surv glioblastoma model.Methods: Transcriptomic alterations of ferroptosis-related genes were studied on naïve U373 and IR-Surv cell populations. To determine the effects of glutathione peroxidase inhibitors, ferroptosis-inducing agent 56 (FIN56) and Ras synthetic lethal 3 (RSL3), on the cells, several properties were assessed, including colony formation, cell viability and lipid peroxidation.Results: Results from the transcriptomic analysis identified ferroptosis as a critical mechanism after radiation exposure in glioblastoma. Our findings also identified the role of ferroptosis inducers (FINs) in IR-survivor cells and suggested using FINs to treat glioblastoma.Conclusion: FINs serve an important role in radioresistant cells; thus, the results of the present study may contribute to improving survival in patients with glioblastoma.

Introduction: Male breast cancer (MBC) accounts for 0.5%-1% of all breast cancers diagnosed worldwide. However, its biological characteristics can be distinguished from that of female breast cancer (FBC).Case Representation: The diagnostic and treatment approaches for MBC are mainly similar to that of FBC due to the lack of male breast cancer-related studies, clinical trials, and literature. An increasing number of retrospective and prospective studies have been conducted to clarify the individualized care for MBC. Herein, we report three cases of advanced MBC to describe the diagnostic approaches, treatment process, and survival prognosis.Conclusion: MBC patients had older age, later stage at first diagnosis, higher expression of hormone receptors, and poor prognosis. A literature review was conducted to determine the incidence, risk factors, disease features, diagnosis, treatment, survival, and management of MBC.