Abstract
One of the major causes of chemotherapy failure in cancer treatment is multidrug resistance (MDR) which is mediated by the ABCB1/P-glycoprotein. Previously, through the use of an extensive screening process, we found that vardenafil, a phosphodiesterase 5 (PDE-5) inhibitor significantly reverses MDR in ABCB1 overexpressing cancer cells, and its efficacy was greater than that of tadalafil, another PDE-5 inhibitor. The present study was designed to determine the reversal mechanisms of vardenafil and tadalafil on ABC transporters-mediated MDR. Vardenafil or tadalafil alone, at concentrations up to 20 µM, had no significant toxic effects on any of the cell lines used in this study, regardless of their membrane transporter status. However, vardenafil when used in combination with anticancer substrates of ABCB1, significantly potentiated their cytotoxicity in ABCB1 overexpressing cells in a concentration-dependent manner, and this effect was greater than that of tadalafil. The sensitivity of the parenteral cell lines to cytotoxic anticancer drugs was not significantly altered by vardenafil. The differential effects of vardenafil and tadalafil appear to be specific for the ABCB1 transporter as both vardenafil and tadalafil had no significant effect on the reversal of drug resistance conferred by ABCC1 (MRP1) and ABCG2 (BCRP) transporters. Vardenafil significantly increased the intracellular accumulation of [3H]-paclitaxel in the ABCB1 overexpressing KB-C2 cells. In addition, vardenafil significantly stimulated the ATPase activity of ABCB1 and inhibited the photolabeling of ABCB1 with [125I]-IAAP. Furthermore, Western blot analysis indicated the incubation of cells with either vardenafil or tadalafil for 72 h did not alter ABCB1 protein expression. Overall, our results suggest that vardenafil reverses ABCB1-mediated MDR by directly blocking the drug efflux function of ABCB1.
Highlights
The resistance of tumor cells to a variety of structurally and mechanistically unrelated cytotoxic drugs, known as multidrug resistance (MDR), is one of the major obstacles in the successful treatment of cancer [1]
The results indicated that both vardenafil and tadalafil did not inhibit the growth of any of the cell lines used in this study at concentrations up to 20 mM
The present study demonstrates for the first time that vardenifil, a phosphodiesterase type-5 (PDE-5) inhibitor used in the treatment of male erectile dysfunction, reverses ABCB1-mediated MDR in a concentration-dependent manner
Summary
The resistance of tumor cells to a variety of structurally and mechanistically unrelated cytotoxic drugs, known as multidrug resistance (MDR), is one of the major obstacles in the successful treatment of cancer [1]. One of the known causes of MDR is overexpression of the ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1/P-gp), multidrug resistance proteins (ABCCs/MRPs) and breast cancer resistant protein (ABCG2/BCRP) These transporters actively efflux a variety of structurally and functionally diverse chemotherapeutic drugs out of cancer cells, thereby reducing the intracellular drug accumulation, increasing the likelihood of decreased cytotoxic and unsuccessful treatment [3,4,5,6]. The third-generation inhibitors were more selective for the ABCB1 transporters in ongoing clinical trials 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 anticancer drugs [15]. We examined their effect on other major ABC drug transporters such as MRP1 and BCRP
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