Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

// Yun-Kai Zhang 1, * , Hengyuan Zhang 2, * , Guan-Nan Zhang 1 , Yi-Jun Wang 1 , Rishil J. Kathawala 1 , Rui Si 1 , Bhargav A. Patel 1 , Jinyi Xu 2 , Zhe-Sheng Chen 1 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA 2 Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China * These authors have contributed equally to this work Correspondence to: Zhe-Sheng Chen, e-mail: chenz@stjohns.edu Jin-Yi Xu, e-mail: jinyixu@china.com Keywords: ABC transporter, multidrug resistance, ABCB1, ginsenoside, ocotillol-type triterpenoid derivatives Received: May 05, 2015 Accepted: June 22, 2015 Published: July 04, 2015 ABSTRACT Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20 S , 24 R/S )-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects. In addition, ORA (3 μM) significantly increased the intracellular accumulation of [ 3 H]-paclitaxel by suppressing the efflux function of ABCB1. Meanwhile, both ORA (3 μM) and OSA (3 μM) did not significantly alter the expression level or the subcellular location of ABCB1 protein. Moreover, the ABCB1 ATPase study suggested that ORA had a stronger stimulatory effect on the ATPase activity than OSA. ORA also exhibited a higher docking score as compared with OSA inside transmembrane domain of ABCB1. Overall, we concluded that ORA reverse ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function.