Mechanisms of Drug Resistance in Cancer Chemotherapy: Coordinated Role and Regulation of Efflux Transporters and Metabolizing Enzymes

Abstract

Cancer remains one of the major leading causes of death worldwide. Acquisition of multidrug resistance (MDR) remains a major impediment to successful chemotherapy. As the name implies, MDR is not limited only to one drug but often associated to structurally and functionally unrelated chemotherapeutics. Extensive research and investigations have identified several mechanisms underlying the development of MDR. This process of drug resistance is considered to be multifactorial including decreased drug accumulation, increased efflux, increased biotransformation, drug compartmentalization, modification of drug targets and defects in cellular pathways. In the first part of the review, these pharmacokinetic and pharmacodynamic mechanisms have been described in brief. Although the pathways can act independently, they are more often intertwined. Of the various mechanisms involved, up-regulation of efflux transporters and metabolizing enzymes constitute a major resistance phenotype. This review also provides a general biological overview of important efflux transporters and metabolizing enzymes involved in MDR. Further, synergistic action between efflux transporters and metabolizing enzymes leading to MDR could possibly arise due to two different factors; overlapping substrate specificity and coordinated regulation of their expression. The expression of efflux transporters and metabolizing enzymes is governed by nuclear receptors, mainly pregnane X receptor (PXR). The pharmacological role of PXR and advances in the development of PXR antagonists to overcome MDR are outlined.

JNK pathway inhibition enhances chemotherapeutic sensitivity to Adriamycin in nasopharyngeal carcinoma cells

“…Currently, the screening of agents inducing chemosensitivity is the main method to overcome this problem (20). In the present study, JNK pathway inhibition was shown to cause cytotoxicity on NPC cells, indicating that this signaling pathway exerts a growth promotion function in NPC cells.…”

Novel delivery approaches for cancer therapeutics

“…As a consequence of efflux, drug absorption is reduced and bioavailability of xenobiotics diminishes at the target tumor tissue. In recent reviews we have elaborately discussed the role of these efflux transporters in drug resistance [342]. A list of anticancer agents that are substrate for various efflux transporters is presented in Table 4.…”

“…Our laboratory has examined the strategy of combining ritonavir-a retroviral protease inhibitors with anticancer drugs to control drug efflux, and metabolism thereby allowing sufficient drug entry into tumor cells [342]. Vinblastine mediated induction of efflux transporters (MDR1, MRP2), metabolizing enzyme (CYP3A4) and nuclear receptor (PXR) is reversed in the presence of ritonavir in human colon adenocarcinoma cells (LS-180).…”

Self‐Assembled DNA Nanostructures for Drug Delivery

“…[44] However, traditional anticancer drugs usually suffered from a number of drawbacks, [45,46] such as the poor specificity and severe side effects. In recent decades, drug resistance has also emerged as a great challenge, [47,48] and has become one of the major sources of the failure in clinical cancer treatments. DNA nanostructures are acting as one of the prominent anti-cancer drug vehicles because of a variety of intriguing structural and chemical features, such as complexity-controlled self-assembly, intricate and programmed shapes, suitable sizes and biocompatibility, and more interestingly the structural tenability.…”