Strategies for inhibition of P-glycoproteins for effective treatment of multidrug resistance tumors

Multidrug resistance (MDR) of tumor cells is the main cause of the failure of cancer chemotherapy. It is defined as the resistance of tumor cells to the cytotoxic action of drugs that are structurally and functionally unrelated. Tumor cells carrying MDR phenotype are often associated with overexpression of some of the drug efflux pumps, known as P-glycoprotein (P-gp) pumps and multidrug resistance associated protein (MRP) pumps belonging to the ABC gene superfamily. This review focuses on the various strategies that can be adapted for overcoming MDR of tumor cells like development of anticancer agents that are nonsubstrates to P-gp; development of agents that have faster uptake than their mediated efflux; by interfering with ATP hydrolysis; by altering integrity of the membrane lipids and also by the use of P-gp modulators. Other approach is by controlling the expression of the MDR proteins by various strategies that are discussed in detail. Alternatively, development of colloidal carriers like nanoparticles and liposomes for cytostatics also helps to overcome the MDR associated with tumor cells. The colloidal carriers prevent the recognition of the antitumor agent by the P-gp that is located in the cell membrane and hence will prevent its efflux from the cell. Nanoparticles have demonstrated encouraging results in reversion of MDR. Combining the P-gp modulator and the cytotoxic agent with in a single nanoparticle formulation has been shown to be a very promising approach in reversion of MDR of tumor cells.