Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 22, Issue 16, 2022

Adaptogens were initially recognized as stress-resistance inducing compounds. Recent studies reveal that adaptogens are pleiotropically-acting chemical constituents that can be isolated from traditional herbs. They are gaining increasing attention in cancer chemotherapy. This review summarizes the physiological action of adaptogens isolated from the 9 most widely used traditional herbs implicated in cancer therapy viz., Withania somnifera, Tinospora cordifolia, Rhodiola rosea, Emblica officinalis, Glycyrrhiza glabra, Bacopa monnieri, Asparagus racemosus, Ocimum sanctum, and Panax notoginseng. The studies were identified through a systematic search of major computerized databases such as Pubmed, Embase, Medline, Inflibnet, Google Scholar, and Cochrane Library. Individual names of each herb and biological action were the search terms employed. In this review, we have enlisted the chemical constituents and their mechanism of action in a few organ systems as well as in cancer cells. Studies indicate that the adaptogens isolated from these herbs can be broadly arranged into 2 classes based on their chemical structure. These molecules exert a positive influence on several organ systems such as respiratory, nervous, cardiovascular, immune, and gastrointestinal tracts. It is also clear that adaptogens act as effective chemopreventive agents alone or in combination with chemo drugs in multiple cancers by targeting multiple intracellular target proteins. Therefore, we conclude that adaptogens are versatile ligands capable of eliciting many systemic effects. Their biological functions are complex, varied, and context-dependent in various cancers. This offers great scope for personalized treatment and cancer chemoprevention in the future.

Cancer has emerged as one of the leading causes of death globally, partly due to the steady rise in anticancer drug resistance. Pyrimidine and pyrimidine-fused heterocycles are some of the privileged scaffolds in medicine, as they possess diverse biological properties. Pyrimidines containing azole nucleus possess inestimable anticancer potency and can potentially regulate cellular pathways for selective anticancer activity. The present review outlines the molecular structure of pyrimidine-fused azoles with significant anticancer activity. The structure activity relationship and molecular docking studies have also been discussed. The current review is the first complete compilation of significant literature on the proposed topic from 2016 to 2020. The information contained in this review offers a useful insight to chemists in the design of new and potent anticancer azole-pyrimidine analogues.

Cancer is the most lethal disease that may be found anywhere globally. Approximately 10% of individuals die due to cancer of various types, with 19.3 million new cancer cases and 10 million deaths reported in 2020. More than 100 medications are commercially available for the treatment of cancer, but only a few candidates have high specificity, resulting in several side effects. The scientific community has spent the past decades focusing on drug discovery. Natural resources are used to isolate pharmaceutically active candidates, which are then synthesized in laboratories. More than 60% of all prescribed drugs are made from natural ingredients. Unique five-membered heteroaromatic center motifs with sulfur, oxygen and nitrogen atoms are found in heterocyclic compounds, such as indazole, thiazole, triazole, triazole, and oxazole, and are used as a core scaffold in many medicinally important therapies. Triazole possesses a wide range of pharmacological activities, including anticancer, antibacterial, antifungal, antibiotic, antiviral, analgesic, anti-inflammatory, anti-HIV, antidiabetic, and antiprotozoal activities. Novel triazole motifs with a variety of biological characteristics have been successfully synthesized using versatile synthetic methods. We intend here to facilitate the rational design and development of innovative triazole-based anti-cancer medicines with increased selectivity for various cancer cell lines by providing insight into various ligand-receptor interactions.

The interaction of drugs with proteins plays a very important role in the distribution of the drug. Human serum albumin (HSA) is the most abundant protein in the human body, showing great binding characteristics, and has gained a lot of importance pharmaceutically. It plays an essential role in the pharmacokinetics of a number of drugs; hence, several reports are available on the interaction of drugs with HSA. It can bind to cancer drugs; thus, it is crucial to look at the binding characteristics of these drugs with HSA. Herein, we summarize the binding properties of some anti-cancer drugs by specifically looking into the binding site with HSA. The number of drugs binding at the Sudlow's site I situated in subdomain II A is more than the drugs binding at Sudlow's site II.

Background: Zerumbone (ZER) exerts potent antiproliferative, apoptotic, and antiangiogenic functions against variety of cancer cells. Cisplatin (CIS), a standard chemotherapeutic drug, is effective against different types of cancers. However, the combined effect of ZER and CIS on hepatocellular carcinoma remains unknown. Objective: The present study is attempted to examine the effectiveness of the combination of ZER and CIS in liver cancer in vitro using the hepatocellular carcinoma Huh-7 cell line. Methods: Effect of ZER, CIS, and their combination therapy on cell viability and cytotoxicity was assessed by MTT and LDH leakage assays. Cell cycle and apoptosis analysis were performed by flow cytometry. Quantitative real-time PCR was used to examine the m-RNA expression of genes involved in apoptosis, angiogenesis, and invasion. Caspase activity was studied using commercial kit method in the Huh-7 cell line. Results: Cells exposed to ZER, CIS individually, and both together significantly inhibited cell proliferation with IC50 values of 10 μM for ZER and 3 μM for CIS. The combination treatment of ZER and CIS revealed a synergistic effect with a CI value < 1. CIS treatment, either alone or in combination with ZER, caused cell cycle arrest in the S phase. More importantly, ZER combined with CIS exhibited synergistic effects in up-regulating Bax/Bcl-2 ratio, leading to caspase cascade activation. Conclusion: In conclusion, the current study indicates that the treatment of 4.62 μM of ZER combined with 1.93 μM of CIS in human liver cancer cells exerts synergistic effects on cell growth inhibition, apoptosis induction, angiogenesis, and invasion by modulating gene expression.

Introduction: Ovarian cancer is the deadliest gynecological malignancy, usually not detected until the late stages. In vitro cell culture is a method used to study the behavior of cells in a controlled environment. Turmeric has attracted the attention of scientists due to its anticancer potential. Methods: OVCAR-3 cells were cultured in RPMI medium with 100 units/mL-100 μg/mL of penicillin-streptomycin and 10% foetal bovine serum in a CO2 incubator. Turmeric extract was diluted in DMSO. Different concentrations of turmeric extract were prepared. Annexin-V staining was performed to test the translocation of phosphatidylserine to the outer side of the cell membrane as a clear indicator of apoptosis. Results: Turmeric extract significantly reduced the viability of OVCAR-3 cells both within 24 and 48 hours of exposure. OVCAR-3 cells were treated with IC50 concentration of turmeric extract for 24 hours. 82.60% of cells were viable. The percentages of the dead, early apoptotic, and late apoptotic cells were detected to be 0.80%, 9.70%, and 6.90%, respectively. Untreated OVCAR-3 cells had migration ability. OVCAR-3 cells exposed to an IC50 concentration of turmeric extract for 24 hours did not close the scratch area. Conclusion: In this research, anticancer effects of turmeric have been demonstrated by different analysis methods.

Background: Tongue squamous cell carcinoma is a fatal disease characterized by high invasion and early metastasis. Dihydroartemisinin, an antimalarial drug with multiple biological activities, is reported to be a potential anti-cancer agent. Objective: This study aimed to evaluate the antitumor effect of Dihydroartemisinin on tongue squamous cell carcinoma cells, and to identify the underlying mechanisms of Dihydroartemisinin-induced cell apoptosis. Methods: Here, Cell Counting Kit 8 assay and colony formation assay were conducted to study cell proliferation. Annexin V-FITC/propidium iodide staining and western blot analysis were performed to analyze cell apoptosis. DCFHDA probe was used to measure the generation of cellular reactive oxygen species. Endoplasmic reticulum stress activation was also determined via western blot analysis. Results: The results showed that Dihydroartemisinin substantially inhibited cell proliferation and induced cell apoptosis in vivo. Moreover, reactive oxygen species production and endoplasmic reticulum stress activation were both observed after stimulation with Dihydroartemisinin. However, the reactive oxygen species inhibitor N-acetylcysteine significantly alleviated Dihydroartemisinin-induced endoplasmic reticulum stress and apoptosis. Conclusion: These results imply that Dihydroartemisinin induced cell apoptosis by triggering reactive oxygen speciesmediated endoplasmic reticulum stress in CAL27 cells. In addition, Dihydroartemisinin might be an effective drug for tongue squamous cell carcinoma therapy.

Background: Proteasome inhibitors target different pathways in cells and therefore are promising drugs in cancer therapy. The use of these inhibitors is approved mainly in hematological cancers, and recently many clinical trials and preclinical studies have been conducted on efficacy in solid tumors. Carfilzomib is a second-generation inhibitor and was developed to decrease the side effects of bortezomib. Although there are many valid therapies for breast cancer, resistance and recurrence are inevitable in many cases and the proteasomal system plays an important role in related pathways. Objective: This study is a preliminary work to evaluate the combined effects of bortezomib and carfilzomib in four different breast cancer cells. Methods: MDA-MB-231, MCF-7, UACC-2087, and SKBR-3 cell lines were used. Cell viability was determined using bortezomib and carfilzomib alone and in combination. Combination effect values were determined using the Chou- Talalay method. Apoptosis, proteasome activity, cleaved PARP, and HSP70 expressions were analyzed in the determined doses. Results: The response to the combination of the two inhibitors was different in four cell lines. Apoptosis was significantly higher in combination groups compared to carfilzomib in three cell lines except for SKBR-3, and higher in the combination group compared to bortezomib only in UACC-2087. Combination decreased cleaved PARP levels in MDA-MB-231 and MCF-7 and increased SKBR-3 compared to bortezomib. HSP70 levels decreased in combination with UACC-2087 and SKBR-3 compared to carfilzomib. Conclusion: Taken together, the combination of the two inhibitors was more apoptotic compared to carfilzomib and apoptosis was higher only in UACC-2087 compared to bortezomib. This apoptosis data can not be directly correlated to the degree of proteasome inhibition, PARP cleavage, and HSP70 response.