Multi-drug Resistance in Cancer and New Approaches for Its Overcoming

Abstract

Resistance to chemotherapy is the main obstacle to efficient cancer treatment. The problem of multi-drug resistance (MDR) has been intensively studied for the last three decades. Classically defined as resistance to structurally and/or functionally unrelated drugs, MDR is connected with aggressive, untreatable cancers. There are two types of MDR: inherent (intrinsic) and acquired. Selection pressures within the tumor microenvironment favor the development of intrinsic MDR, while the ordinary dose and schedule chemotherapy practices induce acquired MDR. In recent years, patient-to-patient variability within each type of cancer has arisen as an unsolved problem. Even more, heterogeneous populations of cancer cells within one patient must be considered as a cause of chemotherapy impediment. Several genes and pathways have been found to contribute to the MDR. Tentatively, MDR phenotype could develop from point mutations, gene amplification or other genetic or epigenetic changes that affect biological functions. Therefore, MDR is driven by similar mechanisms as cancerogenesis. This is also supported by the fact that important characteristics of MDR include abnormal tumor vasculature, regions of hypoxia, aerobic glycolysis, and an elevated apoptotic threshold. Understanding these mechanisms and developing agents to target them are important steps in the design of new therapies. Penetration of drugs into the cancer cell is necessary for their lethal pharmacological effect due to the interaction with intracellular target molecules. Decreased activity of membrane-embedded drug uptake as well as increased activity of efflux pumps reduce the intracellular drug accumulation, thereby preventing drug-target interactions. The discovery of the efflux transporter P-glycoprotein (P-gp) in MDR cancer cells prompted the efforts in overcoming drug resistance by inhibition of P-gp. The search for nontoxic anti-cancer agents able to overcome MDR has been an imperative in the field of drug design and discovery for many years. Two main approaches in combating the problem of MDR in cancer include (i) development of agents able to preserve cytotoxic activity toward MDR cancer cells; (ii) development of compounds able to restore the cytotoxicity of classic anti-cancer drugs. In this chapter, we discuss the new findings regarding MDR reversal strategies, the alterations obtained in our artificially developed MDR models and advantages of our different approaches in overcoming MDR.