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.

Keywords: apoptosis; cell adhesion; cell cycle; chemoresistance; small molecules.

Figure 1

Anti-apoptotic mechanisms contributing to chemotherapy resistance in cancer cells. Extrinsic apoptotic pathways in tumors may be suppressed by downregulation of cell surface death receptors or/and overexpression of cFLIP; intrinsic (mitochondrial) apoptosis is blocked by up-regulation of Bcl-2-like proteins, and both pathways can be terminated by IAPs. FADD—FAS associated protein with death domain; DISC—the death-inducing signaling complex; cFLIP—the cellular FLICE (caspase 8)-like inhibitory protein; tBID—truncated Bid protein; MOMP—mitochondrial outer membrane permeabilization; Smac—second mitochondria-derived activator of caspases; Apaf 1—apoptotic protease activating factor 1; IAPs—inhibitor of apoptosis proteins. TRAIL. Note: green arrows—activation, red arrows—suppression, X—blocking.