title: Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.
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 (20S, 24R/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 [3H]-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.
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors: Yun-Kai
authors: YK
authors: Zhang
authors: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors: Hengyuan
authors: H
authors: Zhang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors: Guan-Nan
authors: GN
authors: Zhang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors: Yi-Jun
authors: YJ
authors: Wang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors: Rishil J
authors: RJ
authors: Kathawala
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors: Rui
authors: R
authors: Si
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors: Bhargav A
authors: BA
authors: Patel
authors: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors: Jinyi
authors: J
authors: Xu
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors: Zhe-Sheng
authors: ZS
authors: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D036145:Ginsenosides / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D017239:Paclitaxel / Q000737:chemistry; D014750:Vincristine / Q000737:chemistry
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D036145:Ginsenosides; C524540:ocotillol; D014750:Vincristine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000251:Adenosine Triphosphatases; D017239:Paclitaxel
keywords: ABC transporter; ABCB1; ginsenoside; multidrug resistance; ocotillol-type triterpenoid derivatives