title: BBA, a derivative of 23-hydroxybetulinic acid, potently reverses ABCB1-mediated drug resistance in vitro and in vivo.
abstract: 23-O-(1,4'-Bipiperidine-1-carbonyl)betulinic acid (BBA), a synthetic derivative of 23-hydroxybetulinic acid (23-HBA), shows a reversal effect on multidrug resistance (MDR) in our preliminary screening. Overexpression of ATP-binding cassette (ABC) transporters such as ABCB1, ABCG2, and ABCC1 has been reported in recent studies to be a major factor contributing to MDR. Our study results showed that BBA enhanced the cytotoxicity of ABCB1 substrates and increased the accumulation of doxorubicin or rhodamine123 in ABCB1 overexpressing cells, but had no effect on non ABCB1 substrate, such as cisplatin; what's more, BBA slightly reversed ABCG2-mediated resistance to SN-38, but did not affect the ABCC1-mediated MDR. Further studies on the mechanism indicated that BBA did not alter the expression of ABCB1 at mRNA or protein levels, but affected the ABCB1 ATPase activity by stimulating the basal activity at lower concentrations and inhibiting the activity at higher concentrations. In addition, BBA inhibited the verapamil-stimulated ABCB1 ATPase activity and the photolabeling of ABCB1 with [(125)I] iodoarylazidoprazosin in a concentration-dependent manner, indicating that BBA directly interacts with ABCB1. The docking study confirmed this notion that BBA could bind to the drug binding site(s) on ABCB1, but its binding position was only partially overlapping with that of verapamil or iodoarylazidoprazosin. Importantly, BBA increased the inhibitory effect of paclitaxel in ABCB1 overexpressing KB-C2 cell xenografts in nude mice. Taken together, our findings suggest that BBA can reverse ABCB1-mediated MDR by inhibiting its efflux function of ABCB1, which supports the development of BBA as a novel potential MDR reversal agent used in the clinic.
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Zhang
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.forename: Jun-Jiang
authors.initials: JJ
authors.lastname: Chen
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Sodani
authors.forename: Jiao
authors.initials: J
authors.lastname: Wang
authors.forename: Jaya
authors.initials: J
authors.lastname: Bhatnagar
authors.forename: Ping
authors.initials: P
authors.lastname: Lan
authors.forename: Zhi-Xiong
authors.initials: ZX
authors.lastname: Ruan
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Xiao
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Ye
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D007624:KB Cells / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D002166:Camptothecin; D002945:Cisplatin; D004317:Doxorubicin; D000077146:Irinotecan; D017239:Paclitaxel; D010880:Piperidines; D012333:RNA, Messenger; D014315:Triterpenes; D014700:Verapamil; C580751:23-O-(1,4'-bipiperidine-1-carbonyl)betulinic acid; D000094062:Betulinic Acid; C468651:23-hydroxybetulinic acid; C513055:ABCB1 protein, human