Tetrandrine and fangchinoline,bisbenzylisoquinoline alkaloids from Stephania tetrandra can reverse multidrug resistance by inhibiting P-glycoprotein activity in multidrug resistant human cancer cells |
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| Institution: | 1. Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany;2. College of Science, Liaoning Technical University, Fuxin, Liaoning 123000, China;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Nan Jing Research and Development Center, CTTQ Pharmaceutical Research Institute, Building 9, NO. 699-8, Xuanwu Dadao, Xuanwu District, Nanjing, Jiangsu, PR China;1. Department of Pharmaceutical Sciences, Faculty of Science, Tshwane University of Technology, Private Bag X680, Pretoria 0001, South Africa;2. SAMRC Herbal Drugs Research Unit, Faculty of Science, Tshwane University of Technology, Private Bag X680, Pretoria 0001, South Africa;1. Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;2. Academy and Scientific & Innovative Research (AcSIR), CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;2. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China |
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| Abstract: | The overexpression of ABC transporters is a common reason for multidrug resistance (MDR) in cancer cells. In this study, we found that the isoquinoline alkaloids tetrandrine and fangchinoline from Stephania tetrandra showed a significant synergistic cytotoxic effect in MDR Caco-2 and CEM/ADR5000 cancer cells in combination with doxorubicin, a common cancer chemotherapeutic agent. Furthermore, tetrandrine and fangchinoline increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrate rhodamine 123 (Rho123) and inhibited its efflux in Caco-2 and CEM/ADR5000 cells. In addition, tetrandrine and fangchinoline significantly reduced P-gp expression in a concentration-dependent manner. These results suggest that tetrandrine and fangchinoline can reverse MDR by increasing the intracellular concentration of anticancer drugs, and thus they could serve as a lead for developing new drugs to overcome P-gp mediated drug resistance in clinic cancer therapy. |
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| Keywords: | Tetrandrine Fangchinoline Multidrug resistance (MDR) ABC transporter activity P-glycoprotein (P-gp) |
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