title: Hernandezine, a Bisbenzylisoquinoline Alkaloid with Selective Inhibitory Activity against Multidrug-Resistance-Linked ATP-Binding Cassette Drug Transporter ABCB1.
abstract: The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein, MDR1) is the most studied mechanism of multidrug resistance (MDR), which remains a major obstacle in clinical cancer chemotherapy. Consequently, resensitizing MDR cancer cells by inhibiting the efflux function of ABCB1 has been considered as a potential strategy to overcome ABCB1-mediated MDR in cancer patients. However, the task of developing a suitable modulator of ABCB1 has been hindered mostly by the lack of selectivity and high intrinsic toxicity of candidate compounds. Considering the wide range of diversity and relatively nontoxic nature of natural products, developing a potential modulator of ABCB1 from natural sources is particularly valuable. Through screening of a large collection of purified bioactive natural products, hernandezine was identified as a potent and selective reversing agent for ABCB1-mediated MDR in cancer cells. Experimental data demonstrated that the bisbenzylisoquinoline alkaloid hernandezine is selective for ABCB1, effectively inhibits the transport function of ABCB1, and enhances drug-induced apoptosis in cancer cells. More importantly, hernandezine significantly resensitizes ABCB1-overexpressing cancer cells to multiple chemotherapeutic drugs at nontoxic, nanomolar concentrations. Collectively, these findings reveal that hernandezine has great potential to be further developed into a novel reversal agent for combination therapy in MDR cancer patients.
authors: Sung-Han
authors: SH
authors: Hsiao
authors: Department of Neurosurgery, Chang Gung Memorial Hospital , Tao-Yuan, Taiwan.
authors: Yu-Jen
authors: YJ
authors: Lu
authors: Chun-Chiao
authors: CC
authors: Yang
authors: Wei-Cherng
authors: WC
authors: Tuo
authors: Yan-Qing
authors: YQ
authors: Li
authors: Yang-Hui
authors: YH
authors: Huang
authors: Chia-Hung
authors: CH
authors: Hsieh
authors: Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital , Taipei, Taiwan.
authors: Tai-Ho
authors: TH
authors: Hung
authors: Department of Neurosurgery, Chang Gung Memorial Hospital , Tao-Yuan, Taiwan.
authors: Chung-Pu
authors: CP
authors: Wu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate; D000470:Alkaloids / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000470:Alkaloids; D044182:Benzylisoquinolines; C067193:hernandezine; D000255:Adenosine Triphosphate