Targeting the ABCG2‐overexpressing multidrug resistant (MDR) cancer cells by PPARγ agonists

Background and Purpose Multidrug resistance (MDR), usually mediated by overexpression of efflux transporters such as P‐gp, ABCG2 and/or MRP1, remains a major obstacle hindering successful cancer chemotherapy. There has been great interest in the development of inhibitors towards these transporters to circumvent resistance. However, since the inhibition of transporter is not specific to cancer cells, a decrease in the cytotoxic drug dosing may be needed to prevent excess toxicity, thus undermining the potential benefit brought about by a drug efflux inhibitor. The design of potent MDR modulators specific towards resistant cancer cells and devoid of drug‐drug interactions will be needed to effect MDR reversal. Experimental Approach Recent evidence suggests that the PTEN/PI3K/Akt pathway may be exploited to alter ABCG2 subcellular localization, thereby circumventing MDR. Three PPARγ agonists (telmisartan, pioglitazone and rosiglitazone) that have been used in the clinics were tested for their effect on the PTEN/PI3K/Akt pathway and possible reversal of ABCG2‐mediated drug resistance. Key Results The PPARγ agonists were found to be weak ABCG2 inhibitors by drug efflux assay. They were also shown to elevate the reduced PTEN expression in a resistant and ABCG2‐overexpressing cell model, which inhibit the PI3K‐Akt pathway and lead to the relocalization of ABCG2 from the plasma membrane to the cytoplasma, thus apparently circumventing the ABCG2‐mediated MDR. Conclusions and Implications Since this PPARγ/PTEN/PI3K/Akt pathway regulating ABCG2 is only functional in drug‐resistant cancer cells with PTEN loss, the PPARγ agonists identified may represent promising agents targeting resistant cells for MDR reversal.