A 20(S)-protopanoxadiol derivative overcomes multi-drug resistance by antagonizing ATP-binding cassette subfamily B member 1 transporter function

Abstract

// Gang Chen 1, 2, * , Junhua Liu 3, * , Wantao Chen 1, 2 , Qin Xu 1, 2 , Meng Xiao 1, 2 , Lihong Hu 3 , Li Mao 1, 4 , Xu Wang 1, 2 1 Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China 2 Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, P. R. China 3 Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China 4 Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD 21201, USA * These authors have contributed equally to this work Correspondence to: Xu Wang, e-mail: wxwxw2004@126.com Lihong Hu, e-mail: lhhu@simm.ac.cn Li Mao, e-mail: lmao@umaryland.edu Keywords: multi-drug resistance, ABCB1, chemotherapy, apoptosis, panax ginseng Received: September 14, 2015      Accepted: January 01, 2016      Published: January 25, 2016 ABSTRACT In cancer cells, failure of chemotherapy is often caused by the ATP-binding cassette subfamily B member 1 (ABCB1), and few drugs have been successfully developed to overcome ABCB1-mediated multi-drug resistance (MDR). To suppress ABCB1 activity, we previously designed and synthesized a new series of derivatives based on 20(S)-protopanoxadiol (PPD). In the present study, we investigated the role of PPD derivatives in the function of ABC transporters. Non-toxic concentrations of the PPD derivative PPD12 sensitized ABCB1-overexpressing cells to their anti-cancer substrates better than either the parental PPD or inactive PPD11. PPD12 increased intracellular accumulation of adriamycin and rhodamine123 in resistant cancer cells. Although PPD12 did not suppress the expression of ABCB1 mRNA or protein, it stimulated the activity of ABCB1 ATPase. Because PPD12 is a competitive inhibitor, it was predicted to bind to the large hydrophobic cavity of homology-modeled human ABCB1. PPD12 also enhanced the efficacy of adriamycin against ABCB1-overexpressing KB/VCR xenografts in nude mice. In conclusion, PPD12 enhances the efficacy of substrate drugs in ABCB1-overexpressing cancer cells. These findings suggest that a combination therapy consisting of PPD12 with conventional chemotherapeutic agents may be an effective treatment for ABCB1-mediated MDR cancer patients.