Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 20, Issue 12, 2020

As cancers are one of the most important causes of human morbidity and mortality worldwide, researchers try to discover novel compounds and therapeutic approaches to decrease survival of cancer cells, angiogenesis, proliferation and metastasis. In the last decade, use of special phytochemical compounds and flavonoids was reported to be an interesting and hopeful tactic in the field of cancer therapy. Flavonoids are natural polyphenols found in plant, fruits, vegetables, teas and medicinal herbs. Based on reports, over 10,000 flavonoids have been detected and categorized into several subclasses, including flavonols, anthocyanins, flavanones, flavones, isoflavones and chalcones. It seems that the anticancer effect of flavonoids is mainly due to their antioxidant and anti inflammatory activities and their potential to modulate molecular targets and signaling pathways involved in cell survival, proliferation, differentiation, migration, angiogenesis and hormone activities. The main aim of this review is to evaluate the relationship between flavonoids consumption and cancer risk, and discuss the anti-cancer effects of these natural compounds in human cancer cells. Hence, we tried to collect and revise important recent in vivo and in vitro researches about the most effective flavonoids and their main mechanisms of action in various types of cancer cells.

Background: Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect: In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.

Hydrogels are water-insoluble, hydrophilic, cross-linked, three-dimensional networks of polymer chains having the ability to swell and absorb water but do not dissolve in it, that comprise the major difference between gels and hydrogels. The mechanical strength, physical integrity and solubility are offered by the crosslinks. The different applications of hydrogels can be derived based on the methods of their synthesis, response to different stimuli, and their different kinds. Hydrogels are highly biocompatible and have properties similar to human tissues that make it suitable to be used in various biomedical applications, including drug delivery and tissue engineering. The role of hydrogels in cancer therapy is highly emerging in recent years. In the present review, we highlighted different methods of synthesis of hydrogels and their classification based on different parameters. Distinctive applications of hydrogels in the treatment of cancer are also discussed.

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreatic cancer and leading causes of pancreatic cancer death because of most PDAC patients with advanced unresectable disease at that time, which is remarkably resistant to all forms of chemotherapy and radiotherapy. Objective: PDAC increases the social and patient's family burden. However, the PDAC pathogenesis is not identified. We are trying to uncover the underlying mechanism in the future. Methods: In our research, the drug-resistant cell line was successfully induced in the vitro by progressive concentrations of Afatinib, which we named it as BxPC3-AR. Results: It has been observed that the effect of autophagy was on the resistance of BxPC3-AR to Afatinib. Conclusion: It has been confirmed that autophagy plays a certain role in BxPC3-AR resistance to Afatinib. Our findings provide a new perspective on the role of autophagy in pancreatic ductal adenocarcinoma.

Background: Hesperetin is a natural compound known for its cholesterol-lowering effect and a wide range of pharmacological activities. Objectives: Investigating the potential anticancer activities of Hesperetin in malignant hematolymphoid cell lines HuT78 and MJ, derived from patients with Cutaneous T-Cell Lymphomas (CTCL). Methods: The cytotoxic effect of Hesperetin on two different CTCL cell lines, HuT78 and MJ, was assessed by MTS-based colorimetric assay. Apoptosis, cell cycle, ROS (Reactive Oxygen Species) and molecular analysis were performed using flow-cytometry and immunoblotting. Results: Hesperetin-treated CTCL cells were arrested at the sub-G1 phase of cell cycle with the concomitant decrease in the expression of the cell cycle regulator protein cyclin B. In addition, the study found that the cellular treatment with Hesperetin caused an induction of apoptosis, which was independent of ROS generation. Hesperetin caused a significant decrease in the expression level of anti-apoptotic protein Bcl-xL and an increase in cleaved caspase-3 and PARP proteins in CTCL cells. Furthermore, Hesperetin treatment in CTCL cells down-regulated the expression of Notch1 and phosphorylation of STAT3 (Tyr705) and inhibited NFΚBp65. Conclusion: This study highlights the anticancer properties of Hesperetin. Which induces apoptosis in CTCL cells via STAT3/Notch1/NFΚB mediated signaling pathway, suggesting that further development of this novel class of flavonoid may contribute to new drug discovery for certain hematolymphoid malignancies.

Background: Discovery of small molecules that inhibit tubulin polymerization is an attractive strategy for the development of new and improved anti-proliferative agents. Objective: A series of novel 2-sulfonyl-1,1-diarylethenes were designed towards this end keeping in view the favorable chemical and pharmacological virtues of unsaturated sulfones. Methods: Rapid, convenient and efficient two-step assembly of the designed molecules was achieved by the vicinal iodo-sulfonylation-Suzuki coupling sequence. Results: As hypothesized, these compounds showed good anti-proliferative activity against different tissuespecific cancer cell lines: MCF-7, DU-145, A-549, HepG2, and HeLa. The most active compound, pnitrophenyl ring-bearing analog, exhibited an IC50 value of 0.90μM against A-549 cells. Flow cytometry studies on this derivative revealed that it arrests the cell cycle of A-549 cells at the G2/M phase. This compound exhibited molecular binding to tubulin as well as tubulin polymerization inhibition comparable to that of colchicine. Conclusion: A new class of potent, tubulin binding anticancer agents based on 1,1,-diarylvinyl sulfone scaffold has been designed and synthesized.

Background: Compounds featuring furan nucleus exhibit diverse biological properties. Lots of furan derivatives have been explored as pharmaceutical compounds. Hence it is of great interest to explore furan derivatives and their precursors as antitumor agents. Objective: A series of novel furan derivatives and their precursors (1-36) were synthesized from α-haloketones and β-dicarbonyl compounds. Methods: The reactions between β-dicarbonyl compounds and α-haloketones under basic conditions produced tricarbonyls or dihydrofurans, which were then condensed into their corresponding furan products. Their potential antiproliferative activity in vitro against two human tumor cell lines-cervical (HeLa) and colorectal (SW620) was evaluated using CCK-8 assay. Compounds 1 and 24 were selected for Western blot analysis. Results: Pronounced anti-proliferative effect in the micromolar level was observed for compounds (1, 4, 17, 20, 21, 24, 27, 31 and 32) in HeLa cells, with their IC50 values ranging from 0.08 to 8.79μM. Additionally, furan compounds (24, 26, 32 and 35) had moderate to potent anti-proliferative activity against the SW620 cell line. Furthermore, the possible targets of these compounds were explored by Western blot analysis. The results indicated that the candidates (compounds 1 and 24) exhibited excellent antiproliferative activity, which may be mediated by promoting the activity of PTEN to suppress PI3K/Akt and Wnt/β-catenin signaling. Conclusion: Most of the furan derivatives and their precursors reported herein exhibited moderate to excellent anti-proliferative activity against HeLa cell line and/or SW620 cell line. Compounds 1 and 24, as well as their analogues may be developed as promising anti-cancer agents.

Background: Cisplatin is an important anticancer agent in cancer chemotherapy, but when resistant cells appear, treatment becomes difficult, and the prognosis is poor. Objective: In this study, we investigated the gene expression profile in cisplatin sensitive and resistant cells, and identified the genes involved in cisplatin resistance. Methods: Comparison of gene expression profiles revealed that UBE2L6 mRNA is highly expressed in resistant cells. To elucidate whether UBE2L6 is involved in the acquisition of cisplatin resistance, UBE2L6- overexpressing cells established from cisplatin-sensitive cells and UBE2L6-silenced cells developed from cisplatin- resistant cells were generated, and the sensitivity of cisplatin was examined. Results: The sensitivity of the UBE2L6-overexpressing cells did not change compared with the control cells, but the UBE2L6-silenced cells were sensitized to cisplatin. To elucidate the mechanism of UBE2L6 in cisplatin resistance, we compared the gene expression profiles of UBE2L6-silenced cells and control cells and found that the level of ABCB6 mRNA involved in cisplatin resistance was decreased. Moreover, ABCB6 promoter activity was partially suppressed in UBE2L6-silenced cells. Conclusion: These results suggest that cisplatin-resistant cells have upregulated UBE2L6 expression and contribute to cisplatin resistance by regulating ABCB6 expression at the transcriptional level. UBE2L6 might be a molecular target that overcomes cisplatin resistance.

Background: Bitter Melon Extract (BME) is widely used for the treatment of various diseases worldwide due to its rich phytochemical and antioxidant content. The well-known anti-cancer drug Paclitaxel (PAC) plays a major role in the treatment of various cancer types such as ovarian, breast, and lung cancer. Technetium-99m (99mTc) radiolabeled paclitaxel is emerging as an imaging probe for breast cancer in vivo. 99mTc labeled compounds have been attracting more scientific attention since the achievement of earlier researches in Nuclear Medicine. People consume several types of diets of plant origin without knowing the interaction with radiolabeled compounds or radiopharmaceuticals. Objective: In the current study, we aimed to monitor the potential effects of the BME on the uptake of 99mTc labeled Paclitaxel (99mTc-PAC) against MCF-7 (ER+) and MDA-MB-231 (ER-) cell lines by using in vitro methods. Methods: BME was obtained by the extraction of BM seeds by 80% ethanol. PAC was labeled with 99mTc by stannous chloride (SnCl2) as a reducing agent. Cytotoxicity and incorporation assays were performed on MCF-7 and MDA-MB-231 cells within the cell culture studies. Results: The uptake value of 99mTc-PAC on MCF-7 cells at 240 minutes was 6.20% and BME treated 99mTc- PAC value was 17.39%. Conclusion: It is observed that BME treatment has a significant effect on the uptake of 99mTc-PAC on MCF-7 cells which is a known estrogen receptor-positive breast carcinoma cell line. It is concluded that this effect could be due to the estrogen receptor-dependent interaction of BME.

Background: Dysregulations of the WNT pathway are implicated in the malignant transformation of different types of neoplasia. WNT7A is expressed in normal peripheral lymphocytes, but is decreased in the tumoral counterpart. Furthermore, the treatment of leukemic cells with recombinant WNT7A decreases proliferation, suggesting its possible use as a therapeutic biomolecule. This study aimed to evaluate the concomitant action of WNT7A and different chemotherapeutic agents over proliferation and cell death of leukemia/ lymphoma derived cell lines. Methods: Ectopic expression of WNT7A was induced in CEM and BJAB cell lines by using a lentiviral system. RNA expression was analyzed by microarrays and qPCR, and protein expression was determined by Western Blot. Cell proliferation was measured by cell counting, metabolic activity by WST-1 assay, cell death and DNA content by flow cytometry. Results: WNT7A ectopic expression was shown to decrease cell proliferation, but the apoptosis rate of leukemic cells was not altered. Moreover, these cells acquired resistance to doxorubicin, vincristine and MG-132. Cell cycle analysis reveals a decrease in G1 and an increase in S and G2 phases with a further upregulation of senescence- associated genes. Microarray analysis reveals that most gene expression changes were related to cancer and metabolic associated pathways. All those changes appear to be independent of the WNT canonical pathway regulation. Conclusion: WNT7A negatively regulates cell proliferation in leukemic cell lines and promotes resistance to chemotherapeutic agents by inducing a senescence-like phenotype independently of the WNT canonical pathway.