title: Butorphanol, a synthetic opioid, sensitizes ABCB1-mediated multidrug resistance via inhibition of the efflux function of ABCB1 in leukemia cells.
abstract: Multidrug resistance (MDR) remains a formidable challenge in the use of chemotherapy and represents a powerful obstacle to the treatment of leukemia. ATP-binding cassette subfamily B member 1 (ABCB1) is a recognized factor which causes MDR and is closely related to poor outcome and relapse in leukemia. Ongoing research concerning the strategy for inhibiting the abnormally high activity of the ABCB1 transporter is critically needed. In the present study, we sought to elucidate the interaction between ABCB1 transporter and butorphanol. Our results showed that butorphanol significantly antagonized ABCB1-mediated drug efflux and increased the intracellular drug concentration by inhibiting the transport activity of ABCB1 in leukemia cells. Mechanistic investigations demonstrated that butorphanol did not alter the protein expression or localization of ABCB1 in HL60/VCR and K562/ADR cells. Furthermore, homology modeling indicated that butorphanol could fit into the large drug-binding cavity of ABCB1 and form a binding conformation. In conclusion, butorphanol reversed the ABCB1-mediated MDR in leukemia cells by directly suppressing the efflux activity of ABCB1.
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shan
authors.affiliation: School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Min-Yue
authors.initials: MY
authors.lastname: Qi
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Xiu
authors.affiliation: Department of Anesthesiology, Qinghai University Affiliated Hospital, Xining, Qinghai 810001, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Shi-Zhe
authors.initials: SZ
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Qinghai University Affiliated Hospital, Xining, Qinghai 810001, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Kang-Qing
authors.initials: KQ
authors.lastname: Xu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002077:Butorphanol / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D004317:Doxorubicin; D017239:Paclitaxel; D002077:Butorphanol