Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells

Abstract

Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment.

Anticancer Effects of Wild Mountain Mentha longifolia Extract in Adrenocortical Tumor Cell Models

“…Differently in H295R cells, ME seemed not to impact on both MAPK and PI3k/Akt signaling pathways. This fact suggests that any specific effect of the extract could reside in other pathways not analyzed in this work (Xia et al, 2014;Alimbetov et al, 2018). As expected, mitotane alone or combined with ME decreased the reactivity of Erk1/2 and Akt in H295R cells, as already demonstrated (Bertazza et al, 2019).…”

Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro

“…Moreover, Lavendustin A reduced neovascularization in a rat model, potentially reducing the engraftment of new vessels in tumors [138]. For D7: GF109203X, an inhibitor of protein kinase C, reduced migration and invasion of lung carcinoma cells was reported [139,140]. However, the same substance showed an increased proliferation of endometrial cancer [141].…”

Metabolic Plasticity in Chemotherapy Resistance

“…Resistance constitutes a lack of response to drug-induced tumor growth inhibition and it may be inherent to a subpopulation of cancer cells or can be acquired as a consequence of drug exposure. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion (104). Reported chemoresistance mechanisms include: altered drug membrane transport, mutation, increased expression of drug targets, decreased drug activation, increased drug degradation due to altered expression of drug-metabolizing enzymes, drug inactivation due to conjugation with glutathione, altered drug subcellular redistribution, drug interactions, enhanced DNA repair, overexpression of anti-apoptotic genes, inactivation of apoptotic gene products, among others (105).…”