Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 20, Issue 18, 2020

Background: Vitamin D (Vit D) serves as a precursor to the potent steroid hormone calcitriol, which regulates numerous genes that control homeostasis, epithelial cell differentiation, proliferation, and apoptosis. Low level of Vit D is implicated in the development and progression of several diseases including bone fractures, cardiovascular disease, diabetes mellitus, and cancers. The present review highlights the role of vitamin D in cancer with a particular emphasis on genetic variants related to Vit D metabolism as well as clinical trials of Vit D supplementation as a potential therapeutic option in the treatment of cancer patients. Methods: Data were collected following an electronic search in the Web of Science, Medline, PubMed, and Scopus databases by using some keywords such as “cancer”, “tumor”, “malignancy”, “vitamin D”, “cholecalciferol” and “calcitriol”. Results: The collected evidence from the studies revealed a consistent and strong association between Vit D status and cancer risk and survival. The associations between Vit D-related genetic variants and cancer survival support the hypothesis that Vit D may affect cancer outcomes. The mechanisms whereby Vit D reduces cancer risk and increases survival are regulation of cellular differentiation, proliferation and apoptosis as well as decreased angiogenesis in tumor microenvironment and inhibition of metastasis. Conclusion: There is a paucity of evidence-based recommendations for the optimal 25(OH)D levels in patients with cancer and the role of Vit D supplementation for primary or secondary prevention of cancer. Well-designed and sufficiently powered randomized clinical trials are necessary to assess the clinical application of Vit D in enhancing the clinical efficacy of standard and adjuvant chemotherapy regimens.

Background: Cancer is spreading all over the world, and it is becoming the leading cause of major deaths. Today’s most difficult task for every researcher is to invent a new drug that can treat cancer with minimal side effects. Many factors, including pollution, modern lifestyle and food habits, exposure to oncogenic agents or radiations, enhanced industrialization, etc. can cause cancer. Treatment of cancer is done by various methods that include chemotherapy, radiotherapy, surgery and immunotherapy in combination or singly along with kinase inhibitors. Most of the anti-cancer drugs use the concept of kinase inhibition. Objective: The number of drugs being used in chemotherapy has heterocycles as their basic structure in spite of various side effects. Medicinal chemists are focusing on nitrogen-containing heterocyclic compounds like pyrrole, pyrrolidine, pyridine, imidazole, pyrimidines, pyrazole, indole, quinoline, oxadiazole, azole, benzimidazole, etc. as the key building blocks to develop active biological compounds. The aim of this study is to attempt to compile a dataset of nitrogen-containing heterocyclic anti-cancer drugs. Methods: We adopted a structural search on notorious journal publication websites and electronic databases such as Bentham Science, Science Direct, PubMed, Scopus, USFDA, etc. for the collection of peer-reviewed research and review articles for the present review. The quality papers were retrieved, studied, categorized into different sections, analyzed and used for article writing. Conclusion: As per FDA databases, nitrogen-based heterocycles in the drug design are almost 60% of unique small-molecule drugs. Some of the nitrogen-containing heterocyclic anti-cancer drugs are Axitinib, Bosutinib, Cediranib, Dasatanib (Sprycel®), Erlotinib (Tarceva®), Gefitinib (Iressa®), Imatinib (Gleevec®), Lapatinib (Tykerb ®), Linifanib, Sorafenib (Nexavar®), Sunitinib (Sutent®), Tivozanib, etc. In the present review, we shall focus on the overview of nitrogen-containing heterocyclic active compounds as anti-cancer agents.

Background: Paclitaxel (PTX) has been clinically used for several years due to its good therapeutic effect against cancers. Its poor water-solubility, non-selectivity, high cytotoxicity to normal tissue and worse pharmacokinetic property limit its clinical application. Objective: To review the recent progress on the PTX delivery systems. Methods: In recent years, the copolymeric nano-drug delivery systems for PTX are broadly studied. It mainly includes micelles, nanoparticles, liposomes, complexes, prodrugs and hydrogels, etc. They were developed or further modified with target molecules to investigate the release behavior, targeting to tissues, pharmacokinetic property, anticancer activities and bio-safety of PTX. In the review, we will describe and discuss the recent progress on the nano-drug delivery system for PTX since 2011. Results: The water-solubility, selective delivery to cancers, tissue toxicity, controlled release and pharmacokinetic property of PTX are improved by its encapsulation into the nano-drug delivery systems. In addition, its activities against cancer are also comparable or high when compared with the commercial formulation. Conclusion: Encapsulating PTX into nano-drug carriers should be helpful to reduce its toxicity to human, keeping or enhancing its activity and improving its pharmacokinetic property.

Background: Chemoresistance is a vital problem in cancer therapy where cancer cells develop mechanisms to encounter the effect of chemotherapeutics, resulting in cancer recurrence. In addition, chemotherapy- resistant leads to the formation of a more aggressive form of cancer cells, which, in turn, contributes to the poor survival of patients with cancer. Objective: In this review, we aimed to provide an overview of how the therapy resistance property evolves in cancer cells, contributing factors and their role in cancer chemoresistance, and exemplified the problems of some available therapies. Methods: The published literature on various electronic databases including, Pubmed, Scopus, Google scholar containing keywords cancer therapy resistance, phenotypic, metabolic and epigenetic factors, were vigorously searched, retrieved and analyzed. Results: Cancer cells have developed a range of cellular processes, including uncontrolled activation of Epithelial- Mesenchymal Transition (EMT), metabolic reprogramming and epigenetic alterations. These cellular processes play significant roles in the generation of therapy resistance. Furthermore, the microenvironment where cancer cells evolve effectively contributes to the process of chemoresistance. In tumour microenvironment immune cells, Mesenchymal Stem Cells (MSCs), endothelial cells and cancer-associated fibroblasts (CAFs) contribute to the maintenance of therapy-resistant phenotype via the secretion of factors that promote resistance to chemotherapy. Conclusion: To conclude, as these factors hinder successful cancer therapies, therapeutic resistance property of cancer cells is a subject of intense research, which in turn could open a new horizon to aim for developing efficient therapies.

The Ras association domain family 10(RASSF10), a tumor suppressor gene, is located on human chromosome 11p15.2, which is one of the members homologous to other N-terminal RASSF families obtained through structural prediction. RASSF10 plays an important role in inhibiting proliferation, invasion, and migration, inducing apoptosis, making cancer cells sensitive to docetaxel, and capturing G2/M phase. Some studies have found that RASSF10 may inhibit the occurrence and development of tumors by regulating Wnt/β-catenin, P53, and MMP2. Methylation of tumor suppressor gene promoter is a key factor in the development and progression of many tumors. Various methylation detection methods confirmed that the methylation and downregulation of RASSF10 often occur in various tumors, such as gastric cancer, lung cancer, colon cancer, breast cancer, and leukemia. The status of RASSF10 methylation is positively correlated with tumor size, tumor type, and TNM stage. RASSF10 methylation can be used as a prognostic factor for overall survival and disease-free survival, and is also a sign of tumor diagnosis and sensitivity to docetaxel chemotherapy. In this review, we mainly elucidate the acknowledged structure and progress in the verified functions of RASSF10 and the probably relevant signaling pathways.

The tendency of using herbs extracts or natural compounds extracted from herbs for preventing or treating different illnesses, including cancer, continues to be an alternative to drug use. Many studies of plant compounds aimed at finding substances with selective cytotoxicity on abnormal cells. Phenolic compounds, as important secondary metabolites from plants, are one of them. In this review, the recent literature data from the past five years about anticancer/antitumor effect of flavonoids and tannins extracted from medicinal plants are surveyed. The cytostatic/antitumor effects of the individual compounds extracted from plants and/or of the plants' polyphenolic extracts are considered, in order to point out the most significant constituents or plants with anticancer potential. The most important results concerning these compounds and their derivatives in cancer prevention and treatment, the importance of their chemical structure, their mechanism of action in vitro and in vivo, and some bioavailability aspects are discussed.

Phthalazinones are important nitrogen-rich heterocyclic compounds which have been a topic of considerable medicinal interest because of their diversified pharmacological activities. This versatile scaffold forms a common structural feature for many bioactive compounds, which leads to the design and development of novel anticancer drugs with fruitful results. The current review article discusses the progressive development of novel phthalazinone analogues that are targets for various receptors such as PARP, EGFR, VEGFR-2, Aurora kinase, Proteasome, Hedgehog pathway, DNA topoisomerase and P-glycoprotein. It describes mechanistic insights into the anticancer properties of phthalazinone derivatives and also highlights various simple and economical techniques for the synthesis of phthalazinones.

Background: Hybridization of coumarin moiety with additional antitumor pharmacophores is an auspicious stratagem to afford precious therapeutic interference for the medication of cancer. Objective: The present study aimed to evaluate the antitumor activity of ethyl 4-(7-hydroxy-4-methyl-2- oxoquinolin-1-ylamino)-coumarin-3-carboxylate against Ehrlich Ascites Carcinoma (EAC) cells in the peritoneal cavity of female mice. Methodology: Molecular docking was used to predict the binding between the test compound and the receptor of breast cancer mutant 3HB5-oxidoreductase, as well as the viability of tumor cells and life span prolongation. The total anti-oxidant capacity was evaluated in the liver and kidneys. Serum alanine transaminase, aspartate transaminase, albumin, total protein, creatinine, and urea were estimated. The concentrations of Bcl-2 and Bax were measured in the liver and kidney tissues. Histopathological examination of the liver and kidney tissues was also carried out. Results: EAC-bearing mice injected with the test compound showed a highly significant decrease in tumor cell viability by 100%, compared to the EAC control. Also, it exhibited significant anti-oxidant and apoptotic agents through the results of total anti-oxidant capacity and apoptosis assays. Confirmed by histological examination, the results of the liver and kidney function tests revealed that the test compound had no harmful effect on either of the organs. The docking investigation disclosed an auspicious interaction between the test compound and the receptor (3HB5). To confirm these results, correlations between different parameters were carried out. It was found that there were significant positive and negative correlations between the parameters. Conclusion: Hybrid molecules containing coumarin and quinolinone exhibited a potential antitumor effect against EAC cells by the induction of apoptosis and anti-oxidant activities. Results of liver and kidney function tests and the histopathological study revealed that the administration of the test compound nullified most of the pathological alterations induced by EAC cells in mice. Based on these findings, the test compound can be developed as an effective chemotherapeutic agent.

Background: Salinomycin, an ionophore antibiotic, is known to be an effective agent in reducing the viability of Glioblastoma (GBM) cells. The combination of salinomycin with other chemotherapeutic drugs would help to overcome the drug resistance of GBM cells. Objective: This study aims to test the combinatorial effect of salinomycin and AZD3463 in T98G GBM cells. Methods: The cytotoxic effects of drugs on T98G GBM cells were determined by using WST-8 assay. Flow cytometry was used to identify apoptosis and cell cycle profiles after treatments. Real-time PCR was used to portray mRNA expression profiles of genes in the Wnt-signaling pathway after treatments. Results: IC50 concentrations of AZD3463 and salinomycin were 529nM and 7.3μM for 48h, respectively. The combination concentrations of AZD3463 and salinomycin were 3.3μM and 333nM, respectively. The combination treatment showed a synergistic effect on reducing the viability of GBM cells. AZD3463, salinomycin, and their combination induced apoptosis in 1.2, 1.4, and 3.2 folds, respectively. AZD3463 and the combination treatment induced the cell cycle arrest at the G1 phase. Salinomycin and AZD3463 treatments, either alone or in combination, resulted in the downregulation or upregulation of mRNA expression levels of genes in the Wntsignaling pathway. Conclusion: Salinomycin, AZD3463, and their combination may inhibit proliferation and induce apoptosis in GBM cells due to a decrease in expression levels of genes acting in both the canonical and non-canonical Wnt signaling pathways. The Wnt signaling pathway may be involved in salinomycin-AZD3463 drug interaction.

Objective: Zoledronic Acid (ZA) is one of the common treatment choices used in various boneassociated conditions. Also, many studies have investigated the effect of ZA on Osteoblastic-Differentiation (OSD) of Mesenchymal Stem Cells (MSCs), but its clear molecular mechanism(s) has remained to be understood. It seems that the methylation of the promoter region of key genes might be an important factor involved in the regulation of genes responsible for OSD. The present study aimed to evaluate the changes in the mRNA expression and promoter methylation of central Transcription Factors (TFs) during OSD of MSCs under treatment with ZA. Materials and Methods: MSCs were induced to be differentiated into the osteoblastic cell lineage using routine protocols. MSCs received ZA during OSD and then the methylation and mRNA expression levels of target genes were measured by Methylation Specific-quantitative Polymerase Chain Reaction (MS-qPCR) and real-time PCR, respectively. The osteoblastic differentiation was confirmed by Alizarin Red Staining and the related markers to this stage. Results: Gene expression and promoter methylation level for DLX3, FRA1, ATF4, MSX2, C/EBPζ, and C/EBPa were up or down-regulated in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21. ATF4, DLX3, and FRA1 genes were significantly up-regulated during the OSD processes, while the result for MSX2, C/EBPζ, and C/EBPa was reverse. On the other hand, ATF4 and DLX3 methylation levels gradually reduced in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21, while the pattern was increasing for MSX2 and C/EBPa. The methylation pattern of C/EBPζ was upward in untreated groups while it had a downward pattern in ZA-treated groups at the same scheduled time. The result for FRA1 was not significant in both groups at the same scheduled time (days 0-21). Conclusion: The results indicated that promoter-hypomethylation of ATF4, DLX3, and FRA1 genes might be one of the mechanism(s) controlling their gene expression. Moreover, we found that promoter-hypermethylation led to the down-regulation of MSX2, C/EBP-ζ and C/EBP-α. The results implicate that ATF4, DLX3 and FRA1 may act as inducers of OSD while MSX2, C/EBP-ζ and C/EBP-α could act as the inhibitor ones. We also determined that promoter-methylation is an important process in the regulation of OSD. However, yet there was no significant difference in the promoter-methylation level of selected TFs in ZA-treated and control cells, a methylation- independent pathway might be involved in the regulation of target genes during OSD of MSCs.

Background: Breast cancer is the most common kind of cancer among women in the world. Despite major cancer therapy successes in recent years, cancer cells usually develop mechanisms to survive chemotherapy- induced cell death. Therefore, new strategies are needed to reverse cancer chemoresistance. Objective: The aim of this study was to investigate the effect of a recently-synthesized ferrocene derivative named 1-ferrocenyl-3-(4-methylsulfonylphenyl)propen-1-one (FMSP) on cisplatin resistance in MCF-7 cells, focusing on its inhibitory effects on Multi-Drug Resistance-1 (MDR-1) and inflammatory-related STAT3 pathway. Methods: Cisplatin-resistant MCF-7 cells were developed and the effect of cisplatin and FMSP on cell viability was examined by MTT assay. RT-PCR and Western blotting analyses were performed to assess the gene and protein expression of MDR-1 as well as phosphorylation of JAK2 and STAT3. Results: Overexpression of MDR1 as well as a marked increase in the level of phosphorylated STAT3 was observed in cisplatin-resistant MCF-7 (MCF-7R) cells. FMSP successfully reduced the MCF-7R cell viability and reversed both MDR1 expression and STAT3 phosphorylation status through which sensitivity of MCF-7R cells to cisplatin treatment was regained. Conclusion: Our results indicated that FMSP may be considered as a promising therapeutic agent for the prevention and management of chemoresistance in breast cancer cells.

Background: Conventional cancer therapeutics has enormous toxicity and severe side effects that generate multi-drug resistance. Therefore, an urgent need exists for new alternative therapeutic agents for cancer treatment. Cepharanthin (CEP) has anti-cancer potential but has poor aqueous solubility, which limits its clinical use. Nanosuspensions (NS) are attractive as insoluble drug delivery systems. Objectives: In this study, we used D-alpha Tocopherol acid Polyethylene Glycol Succinate (TPGS), Polyvinylpyrrolidone (PVP) VA64, and Croscamellose Sodium (CCS) as stabilizers to produce TPGS-CEP-NS, PVP VA64-CEP-NS, and CCS-CEP-NS by wet-milling technology, and then characterized the NS and evaluated their functional activities in vitro. Methods: CEP Nanosuspensions (CEP-NS) were prepared by the wet-milling method. The prepared NS were characterized by particle size distribution, zeta potential, morphology, surface properties, and molecular interactions. The NS were evaluated for their effects on HepG2 cells in vitro. The evaluations included assessment of cellular cytotoxicity, cellular apoptosis, NS uptake by cells, and mitochondrial membrane potential changes. Results: CEP-NS showed an appropriate particle size and were physically stable. All CEP-NS exhibited HepG2 enhanced anti-proliferative effects by reducing cell viability, enhanced cellular uptake, induced cellular apoptosis, and mitochondrial membrane potential loss. Conclusions: CEP-NS may be effective therapeutic agents for the treatment of hepatocellular carcinoma.

Background: Searching for new cytotoxic agents with apoptosis induction may represent a viable strategy for cancer treatment to overcome the increased resistance to available anticancer agents. Objective: The purpose of the current study was aimed at preparation and anticancer evaluation of two new series of 2H-quinolinone and halogenated 2H-quinolinone derivatives against two cancer cell lines. Methods: Two new series of 2H-quinolinone and halogenated 2H-quinolinone derivatives were prepared and screened for their cytotoxicity against breast MCF-7 and liver HepG-2 cancer cell lines as well as normal breast MCF-10a. Results: The tested molecules revealed good cytotoxicity and selectivity toward cancer cell lines relative to normal cells. These compounds were analyzed by DNA flow cytometry on MCF-7 cells. They were found to cause G2/M phase arrest and induced apoptosis at the pre-G1 phase. In addition, increased caspase 3/7 activity and decreased osteopontin expression verified the apoptotic activity. Conclusion: The potent compounds discovered in this study can be a hit for the discovery of new cytotoxic agents and are worthy of further investigation.

Background: Ruxolitinib is a selective JAK1/2 inhibitor approved by the FDA for myelofibrosis in 2014 and nowadays, comprehensive investigations on the potential of the agent as a targeted therapy for haematological malignancies are on the rise. In multiple myeloma which is a cancer of plasma cells, the Interleukin- 6/JAK/STAT pathway is emerging as a therapeutic target since the overactivation of the pathway is associated with poor prognosis. Objective: In this study, our purpose was to discover the potential anticancer effects of ruxolitinib in ARH-77 multiple myeloma cell line compared to NCI-BL 2171 human healthy B lymphocyte cell line. Methods: Cytotoxic effects of ruxolitinib in ARH-77 and NCI-BL 2171 cells were determined via WST-1 assay. The autophagy mechanism induced by ruxolitinib measured by detecting autophagosome formation was investigated. Apoptotic effects of ruxolitinib were analyzed with Annexin V-FITC Detection Kit and flow cytometry. We performed RT-qPCR to demonstrate the expression changes of the genes in the IL-6/JAK/STAT pathway in ARH-77 and NCI-BL 2171 cells treated with ruxolitinib. Results: We identified the IC50 values of ruxolitinib for ARH-77 and NCI-BL 2171 as 20.03 and 33.9μM at the 72nd hour, respectively. We showed that ruxolitinib induced autophagosome accumulation by 3.45 and 1.70 folds in ARH-77 and NCI-BL 2171 cells compared to the control group, respectively. Treatment with ruxolitinib decreased the expressions of IL-6, IL-18, JAK2, TYK2, and AKT genes, which play significant roles in MM pathogenesis. Conclusion: All in all, ruxolitinib is a promising agent for the regulation of the IL-6/JAK/STAT pathway and interferes with the autophagy mechanism in MM.