Major chemotherapeutic drug metabolizing enzymes thereby reducing the the clearance and metabolism of chemotherapeutic drugs. The third-generation inhibitors were more selective for the ABCB1 transporters in ongoing clinical trials. Nonetheless, some of these compounds produced significant adverse effects and had an unfavorable pharmacokinetic profile, including poor solubility as well as reducing the clearance of clinically used antiIPI-145 cancer drugs. Recent results from our laboratory and others indicate that several tyrosine kinase inhibitors, including imatinib, nilotinib, lapatinib, and erlotinib, can reverse MDR to antineoplastic drugs mediated by ABCtransporters. However, the reversal potential of these TKIs have not been determined in clinical trials. Consequently, it is necessary to develop more efficacious, non-toxic and less expensive compounds to reverse MDR in cancer cells. In the course of our search for compounds that reverse MDR, we found that vardenafil and tadalafil, two phosphodiesterase type-5 inhibitors clinically used in the treatment of male erectile dysfunction, significantly reversed ABCB1-mediated MDR. In the present study, we conducted experiments to ascertain the reversal mechanism of vardenafil and tadalafil in ABCB1 overexpressing cancer cells. In addition, we also examined their effect on other major ABC drug transporters such as MRP1 and BCRP. In another series of experiments, we determined the effect of vardenafil on paclitaxel efflux. The intracellular levels of paclitaxel were measured over a period of 2 h. As expected, a significantly higher concentration of paclitaxel was LY354740 supplier effluxed from the KB-C2 cells compared to KB-3-1 cells, and the amount of effluxed paclitaxel increased with time. At the one hour time point, 70 of the accumulated paclitaxel was effluxed from the KB-C2 cells in the absence of vardenifil, where significantly blocked the efflux function of ABCB1, with 75 of the paclitaxel being retained inside the KB-C2 cells. There was no significant change in the concentration of paclitaxel subjected to efflux in parental KB-3-1 cells in the absence or presence of vardenafil. Thus, vardenifil significantly inhibited paclitaxel efflux from the KB-C2 cells to the extent that efflux from this cell line was comparable to that of the control cells. One of the major mechanisms responsible to MDR in cancer cells is the overexpression of the ABCB1 transporter.. However, currently, none of the ABCB1 inhibitors or modulators have been approved for clinical oncological practice. The present study demonstrates for the first time that vardenifil, a PDE-5 inhibitor used in the treatment of male erectile dysfunction, reverses ABCB1-mediated MDR in a concentration-dependent manner. The magnitude of vardenafils reversal is simila
