1. Academic Validation
  2. CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function

CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function

  • Biochem Pharmacol. 2014 Sep 15;91(2):144-56. doi: 10.1016/j.bcp.2014.07.008.
Shang-jun Tang 1 Li-kun Chen 2 Fang Wang 3 Yun-kai Zhang 4 Zhen-cong Huang 5 Kenneth Kin Wah To 6 Xiao-kun Wang 7 Tanaji T Talele 8 Zhe-sheng Chen 9 Wei-qiang Chen 10 Li-wu Fu 11
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
  • 3 State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: [email protected].
  • 5 State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Chinese University of Hong Kong, New Territories, Hong Kong, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
  • 8 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: [email protected].
  • 9 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: [email protected].
  • 10 Department of General Surgery, Chen Xing Hai Hospital, Guangdong Medical College, Zhongshan, China. Electronic address: [email protected].
  • 11 State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
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.

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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15343
    99.23%, JAK2 Inhibitor
    JAK