title: CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function.
abstract: The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients.
authors: Department of General Surgery, Chen Xing Hai Hospital, Guangdong Medical College, Zhongshan, China; State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: tangshangjun1119@126.com.
authors: Shang-jun
authors: SJ
authors: Tang
authors: State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: chenlk@sysucc.org.cn.
authors: Li-kun
authors: LK
authors: Chen
authors: State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: wangfang0203@163.com.
authors: Fang
authors: F
authors: Wang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: helloyunyun@live.com.
authors: Yun-kai
authors: YK
authors: Zhang
authors: State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: zc271211033@163.com.
authors: Zhen-cong
authors: ZC
authors: Huang
authors: School of Pharmacy, Chinese University of Hong Kong, New Territories, Hong Kong, China. Electronic address: kennethto@cuhk.edu.hk.
authors: Kenneth Kin Wah
authors: KK
authors: To
authors: State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: wxk198708@163.com.
authors: Xiao-kun
authors: XK
authors: Wang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: talelet@stjohns.edu.
authors: Tanaji T
authors: TT
authors: Talele
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: chenz@stjohns.edu.
authors: Zhe-sheng
authors: ZS
authors: Chen
authors: Department of General Surgery, Chen Xing Hai Hospital, Guangdong Medical College, Zhongshan, China. Electronic address: cwq20138@tom.com.
authors: Wei-qiang
authors: WQ
authors: Chen
authors: State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: Fulw@mail.sysu.edu.cn.
authors: Li-wu
authors: LW
authors: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental; D011725:Pyridines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000378:metabolism; D019772:Topotecan / Q000008:administration & dosage / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C567989:CEP 33779; D011725:Pyridines; D014230:Triazoles; D020112:Rhodamine 123; D019772:Topotecan; D004317:Doxorubicin
keywords: ABCB1/P-glycoprotein; CEP-33779; CEP-33779 (PubChem CID: 57336812); Chemotherapeutic agents; Doxorubicin (PubChem CID: 31703) Rhodamine 123 (PubChem CID: 65217); JAK2 inhibitor; Multidrug resistance (MDR); Verapamil (PubChem CID: 62969); Vincristine (PubChem CID: 5978)