title: Bipiperidinyl derivatives of 23-hydroxybetulinic acid reverse resistance of HepG2/ADM and MCF-7/ADR cells.
abstract: Multidrug resistance (MDR) is a major obstacle to successful chemotherapy for cancer; thus, novel MDR reversers are urgently needed. In the present study, we assessed whether two synthetic derivatives of 23-hydroxybetulinic acid, 3,23-O-diacetyl-17-1,4'-bipiperidinyl betulinic amide (DABB) and 3,23-O-dihydroxy-17-1,4'-bipiperidinyl betulinic amide (DHBB), could reverse MDR induced by ATP-binding cassette (ABC) transporters. Using the MTT assay, we found that DABB and DHBB could enhance the cytotoxicities of ABCB1 substrates doxorubicin, vincristine, and paclitaxel in ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells, whereas that of a non-ABCB1 substrate cisplatin was unaffected. The ABCB1 substrate accumulation and efflux assay showed that DABB and DHBB not only enhanced the retention of doxorubicin and rhodamine123 but also inhibited the efflux of rhodamine123. Further mechanistic studies by reverse transcription PCR, western blot, and ABCB1 ATPase activity assay indicated that DABB and DHBB suppressed ABCB1 ATPase activity, but did not alter mRNA or protein expression of ABCB1. ABCB1 siRNA pretreatment attenuated the reversal effect of DABB and DHBB, indicating that their reversal effects were partially dependent on ABCB1. Docking analysis also implied that DABB and DHBB bind directly to ABCB1 at a site partly overlapped with that of verapamil. Taken together, our findings suggest that two bipiperidinyl derivatives of 23-hydroxybetulinic acid reverse ABCB1-mediated MDR through modulation of ABCB1 ATPase activity, thereby inhibiting its efflux function in both HepG2/ADM and MCF-7/ADR cells. These findings may contribute toward the development of novel MDR reversers using DABB and DHBB as adjuvant anticancer chemotherapy.
authors: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University bCancer Center, Sun Yat-Sen University, Guangzhou, China.
authors: Dong-Mei
authors: DM
authors: Zhang
authors: Ying-Jie
authors: YJ
authors: Li
authors: Chang
authors: C
authors: Shu
authors: Zhi-Xiong
authors: ZX
authors: Ruan
authors: Wei-Min
authors: WM
authors: Chen
authors: Anita
authors: A
authors: Yiu
authors: Ying-Hui
authors: YH
authors: Peng
authors: Jiao
authors: J
authors: Wang
authors: Ping
authors: P
authors: Lan
authors: Zhe
authors: Z
authors: Yao
authors: Kwok-Pui
authors: KP
authors: Fung
authors: Li-Wu
authors: LW
authors: Fu
authors: Zhe-Sheng
authors: ZS
authors: Chen
authors: Wen-Cai
authors: WC
authors: Ye
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004317:Doxorubicin; D017239:Paclitaxel; D010880:Piperidines; D020112:Rhodamine 123; D014315:Triterpenes; D014700:Verapamil; D014750:Vincristine; C468651:23-hydroxybetulinic acid; C583383:3,23-O-diacetyl-17-1,4'-bipiperidinyl betulinic amide; D000094062:Betulinic Acid; C583384:3,23-O-dihydroxy-17-1,4'-bipiperidinyl betulinic amide; C513055:ABCB1 protein, human; C510163:CYP3A4 protein, human