Reversal of ABCB1- and ABCG2-mediated drug resistance by sildenafil (Viagra)
Zhe-Sheng (Jason) Chen, College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences
Abstract: Sildenafil is a selective inhibitor of type 5 cGMP-specific phosphodiesterase and is clinically used to treat erectile dysfunction and pulmonary arterial hypertension. Overexpression of ABC transporters such as ABCB1, ABCC1 and ABCG2 is one of the main causes of the development of resistance in cancer cells to chemotherapeutic drugs. However, the effect of sildenafil on these ABC transporters is still unknown. In the present study, we found that sildenafil had differential effects on these transporters. In ABCB1-overexpressing cells, non-toxic doses of sildenafil were found to inhibit resistance to ABCB1 substrate anticancer drugs, as well as significantly increase intracellular accumulation of [3H]-paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil partially reversed resistance to ABCG2 substrate anticancer drugs and increased intracellular accumulation of [3H]-mitoxantrone as well as the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of [3H]-E217βG and [3H]-methotrexate by ABCG2. Sildenafil significantly stimulated ABCB1 ATPase activity but it only slightly stimulated ABCG2 ATPase activity. However, it inhibited photolabeling of both ABCB1 and ABCG2 with [125I]-IAAP. Additionally, sildenafil did not alter the sensitivity of parental, ABCB1- or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drug and had no effect on the function of ABCC1. We also modeled the binding of sildenafil within the large cavity of the transmembrane region of homology model of ABCB1 based on the mouse Abcb1a structure. Overall, we conclude that sildenafil can inhibit the function of ABCB1 and ABCG2, with a stronger effect on ABCB1. These findings suggest that it may be possible to develop potent MDR reversal agents from clinically approved drugs with known side effects and drug interactions.