P-glycoprotein Inhibition as a Therapeutic Approach for Overcoming Multidrug Resistance in Cancer: Current Status and Future Perspectives

Ziyad      Binkhathlan; Afsaneh      Lavasanifar

Abstract

One of the major causes of failure in cancer chemotherapy is multidrug resistance (MDR), where cancer cells simultaneously become resistant to different anticancer drugs. Over-expression of membrane efflux pumps like Pglycoprotein (P-gp) that recognizes different chemotherapeutic agents and transports them out of the cell, plays a major role in MDR. The shortcoming of P-gp inhibitors in clinic has been attributed to their non-specific action on P-gp and/or non-selective distribution to non-target organs that leads to intolerable side effects by the P-gp inhibitor at doses required for P-gp inhibition upon systemic administration. Another major issue is the reduced elimination of P-gp substrates (e.g. anticancer drugs) and intolerable toxicities by anticancer drugs when co-administered with P-gp inhibitors. To overcome these shortcomings, new generation of P-gp inhibitors with improved specificity for P-gp have been developed. More recently, attention has been paid to the use of drug delivery systems primarily to restrict P-gp inhibition to tumor and reduce the non-selective inhibition of P-gp in non-target organs. This review will provide an overview and update on the status of P-gp inhibition approaches and the role of drug delivery systems in overcoming P-gp mediated MDR.

Keywords: Cancer, chemotherapy, drug delivery systems, gene silencing, multidrug resistance, P-glycoprotein, P-glycoprotein inhibitors

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