Current Topics in Medicinal Chemistry - Volume 22, Issue 31, 2022

Background: The failure of anticancer chemotherapy is often due to the development of resistance to a variety of anticancer drugs. This phenomenon is called multidrug resistance (MDR) and is related to the overexpression of ABC transporters, such as P-glycoprotein, multidrug resistance- associated protein 1 and breast cancer resistance protein. Over the past few decades, several ABC protein modulators have been discovered and studied as a possible approach to evade MDR and increase the success of anticancer chemotherapy. Nevertheless, the co-administration of pump inhibitors with cytotoxic drugs, which are substrates of the transporters, does not appear to be associated with an improvement in the therapeutic efficacy of antitumor agents. However, more recently discovered MDR reversing agents, such as the two tetrahydroisoquinoline derivatives tariquidar and elacridar, are characterized by high affinity towards the ABC proteins and by reduced negative properties. Consequently, many analogs of these two derivatives have been synthesized, with the aim of optimizing their MDR reversal properties. Objective: This review aims to describe the MDR modulators carrying the tetraidroisoquinoline scaffold reported in the literature in the period 2009-2021, highlighting the structural characteristics that confer potency and/or selectivity towards the three ABC transport proteins. Results and Conclusion: Many compounds have been synthesized in the last twelve years showing interesting properties, both in terms of potency and selectivity. Although clear structure-activity relationships can be drawn only by considering strictly related compounds, some of the compounds reviewed could be promising starting points for the design of new ABC protein inhibitors.

Colorectal cancer being the second leading cause of cancer-associated deaths has become a significant health concern around the globe. Though there are various cancer treatment approaches, many of them show adverse effects and some compromise the health of cancer patients. Hence, significant efforts are being made for the evolution of a novel biological therapeutic approach with better efficacy and minimal side effects. Current research suggests that the application of peptides in colorectal cancer therapeutics holds the possibility of the emergence of an anticancer reagent. The primary beneficial factors of peptides are their comparatively rapid and easy process of synthesis and the enormous potential for chemical alterations that can be evaluated for designing novel peptides and enhancing the delivery capacity of peptides. Peptides might be utilized as agents with cytotoxic activities or as a carrier of a specific drug or as cytotoxic agents that can efficiently target the tumor cells. Further, peptides can also be used as a tool for diagnostic purposes. The recent analysis aims at developing peptides that have the potential to efficiently target the tumor moieties without harming the nearby normal cells. Additionally, decreasing the adverse effects, and unfolding the other therapeutic properties of potential peptides, are also the subject matter of in-depth analysis. This review provides a concise summary of the function of both natural and synthetically derived peptides in colorectal cancer therapeutics that are recently being evaluated and their potent applications in the clinical field.

Endocrine cancer is an uncontrolled growth of cells in the hormone-producing glands. Endocrine cancers include the adrenal, thyroid, parathyroid, pancreas, pituitary, and ovary malignancy. Recently, there is an increase in the incidence of the most common endocrine cancer types, namely pancreatic and thyroid cancers. Cancer stem cells (CSCs) of endocrine tumors have received more attention due to their role in cancer progression, therapeutic resistance, and cancer relapse. Phytochemicals provide several health benefits and are effective in the treatment of various diseases including cancer. Therefore, finding the natural phytochemicals that target the CSCs will help to improve cancer patients' prognosis and life expectancy. Phytochemicals have been shown to have anticancer properties and are very effective in treating various cancer types. Curcumin is a common polyphenol found in turmeric, which has been shown to promote cellular drug accumulation and increase the effectiveness of chemotherapy. Moreover, various other phytochemicals such as resveratrol, genistein, and apigenin are effective against different endocrine cancers by regulating the CSCs. Thus, phytochemicals have emerged as chemotherapeutics that may have significance in preventing and treating the endocrine cancers.

Background: Metastasis is the world's leading cause of colon cancer morbidity. Due to its heterogeneity, it has been challenging to understand primary to metastatic colon cancer progression and find a molecular target for colon cancer treatment. Objectives: The current investigation aimed to characterize the immune and genotypic profiles of primary and metastatic colon cancer cell lines and identify a molecular target for colon cancer treatment. Methods: Colony-forming potential, migration and invasion potential, cytokine profiling, miRNA, and mRNA expression were examined. Molecular docking for the Wnt signaling proteins with various plant compounds was performed. Results: Colony formation, migration, and invasion potential were significantly higher in metastatic cells. The primary and metastatic cells' local immune and genetic status revealed TGF β-1, IL-8, MIP-1b, I-TAC, GM-CSF, and MCP-1 were highly expressed in all cancer cells. RANTES, IL-4, IL- 6, IFNγ, and G-CSF were less expressed in cancer cell lines. mRNA expression analysis displayed significant overexpression of proliferation, cell cycle, and oncogenes, whereas apoptosis cascade and tumor suppressor genes were significantly down-regulated in metastatic cells more evidently. Most importantly, the results of molecular docking with dysregulated Wnt signaling proteins shows that peptide AGAP and coronaridine had maximum hydrogen bonds to β-catenin and GSK3β with a better binding affinity. Conclusion: This study emphasized genotypic differences between the primary and metastatic colon cancer cells, delineating the intricate mechanisms to understand the primary to metastatic advancement. The molecular docking aided in understanding the future molecular targets for bioactive- based colon cancer therapeutic interventions.