Isoreserpine Reverses Multidrug Resistance Mediated by ABCB1
Pages 188-194
Yang-Hui Huang, Sung-Han Hsiao and Chung-Pu Wu

DOI: http://dx.doi.org/10.6000/1929-2279.2015.04.04.7

Published: 26 November 2015

Abstract: One of the major obstacles to successful cancer chemotherapy is the development of multidrug resistance (MDR) that is associated with the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein/ MDR1). Currently, the most efficient way to overcome ABCB1-mediated MDR in cancer is by direct inhibition of ABCB1 function. Many drugs with known biological activities have been discovered to inhibit the function of ABCB1 and reverse ABCB1-mediated MDR in cancers. However, clinical trial results suggested that many of these clinically active drugs should not be used as ABCB1 modulators due to direct toxicity or undesirable side effects. In this study, we demonstrated that isoreserpine, an indole alkaloid with relatively low toxicity, can significantly inhibit ABCB1-mediated efflux of calcein-AM, a known substrate of ABCB1, in a dose-dependent manner. Moreover, we showed that at non-toxic concentrations, isoreserpine potently reversed ABCB1-mediated resistance to doxorubicin and colchicine in ABCB1-overexpressing human KB-V-1 epidermal cancer cells. Collectively, our findings revealed that by inhibiting the transport function of ABCB1, isoreserpine can restore drug sensitivity of ABCB1-overexpressing cells to conventional chemotherapeutic drugs. In conclusion, isoreserpine should be further developed into a promising reversal agent for the treatment of MDR in ABCB1-overexpressing cancers.

Keywords: Multidrug resistance, Isoreserpine, ABCB1.