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

Shang-jun Tang1, Li-kun Chen2, Fang Wang2

  • 1Department 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.

Biochemical Pharmacology
|July 25, 2014
PubMed

Insights

CEP-33779, a Janus kinase 2 (JAK2) inhibitor, overcomes multidrug resistance (MDR) in cancer cells by directly blocking P-glycoprotein (ABCB1) transport function. This enhances chemotherapy efficacy, offering new therapeutic strategies for MDR cancer patients.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Multidrug resistance (MDR) in cancer, driven by ATP-binding cassette (ABC) transporters like P-glycoprotein (ABCB1), significantly limits chemotherapy effectiveness.
  • CEP-33779 is a small-molecule inhibitor targeting Janus kinase 2 (JAK2).

Purpose of the Study:

  • To evaluate CEP-33779's potential to enhance conventional chemotherapeutic efficacy in MDR cancer cells overexpressing ABCB1, ABCC1, and ABCG2.
  • To elucidate the mechanism by which CEP-33779 affects ABCB1-mediated drug resistance.

Main Methods:

  • Assessing CEP-33779's effect on drug sensitivity and intracellular drug accumulation in ABCB1-overexpressing MDR cells.
  • Investigating CEP-33779's impact on ABCB1 expression, protein and mRNA levels, and ATPase activity.
  • Utilizing homology modeling to predict CEP-33779 binding to ABCB1.
  • Evaluating the in vivo efficacy of CEP-33779 in combination with vincristine using a KBv200 cell xenograft model in nude mice.

Main Results:

  • CEP-33779, at non-toxic concentrations, sensitized ABCB1-overexpressing MDR cells to anticancer drugs.
  • CEP-33779 increased doxorubicin intracellular accumulation and reduced its efflux by inhibiting ABCB1 transport.
  • CEP-33779 stimulated ABCB1 ATPase activity and was predicted to bind within ABCB1's hydrophobic cavity, without altering ABCB1 expression levels.
  • JAK2 inhibition did not affect ABCB1 expression or drug sensitivity.
  • CEP-33779 significantly improved vincristine efficacy in an in vivo xenograft model of ABCB1-mediated drug resistance.

Conclusions:

  • CEP-33779 enhances chemotherapy efficacy in ABCB1-overexpressing MDR cells by directly inhibiting ABCB1 transport function, independent of JAK2 inhibition.
  • These findings support further investigation into combination therapy with CEP-33779 for ABCB1-mediated MDR cancers.
Keywords:
ABCB1/P-glycoproteinCEP-33779CEP-33779 (PubChem CID: 57336812)Chemotherapeutic agentsDoxorubicin (PubChem CID: 31703) Rhodamine 123 (PubChem CID: 65217)JAK2 inhibitorMultidrug resistance (MDR)Verapamil (PubChem CID: 62969)Vincristine (PubChem CID: 5978)

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