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Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib

Guan-Nan Zhang1, Yun-Kai Zhang1, Yi-Jun Wang1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences,St. John's University, Queens, New York, 11439, USA.

Pharmacological Research
|January 30, 2017
PubMed

Insights

Cabozantinib reverses multidrug resistance by inhibiting the ABCG2 transporter. This enhances the efficacy of chemotherapy drugs that are substrates of ABCG2, offering new hope for resistant cancers.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • Cabozantinib is a tyrosine kinase inhibitor approved for certain cancers.
  • Multidrug resistance (MDR) mediated by ABCG2 transporter is a major challenge in cancer therapy.
  • Identifying agents that overcome ABCG2-mediated MDR is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate cabozantinib's ability to modulate ATP-binding cassette subfamily G member 2 (ABCG2) transporter function.
  • To determine if cabozantinib can sensitize cancer cells resistant to ABCG2 substrate drugs.
  • To explore the mechanism by which cabozantinib affects ABCG2-mediated drug efflux.

Main Methods:

  • Utilized drug-selected resistant cell lines and ABCG2-overexpressing stable cell lines.
  • Assessed the effect of cabozantinib on cell sensitization to ABCG2 substrate antineoplastic drugs (mitoxantrone, SN-38, topotecan) at non-toxic concentrations.
  • Performed molecular docking analysis to investigate cabozantinib's interaction with the ABCG2 transporter.

Main Results:

  • Cabozantinib (3-5μM) sensitized ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan.
  • Cabozantinib reversed ABCG2-mediated multidrug resistance by antagonizing ABCG2's drug efflux function, not by downregulating its expression.
  • Molecular docking confirmed cabozantinib binds to the drug-binding site of ABCG2.

Conclusions:

  • Cabozantinib inhibits the function of the ABCG2 transporter.
  • This inhibition enhances the efficacy of ABCG2 substrate antineoplastic agents.
  • Cabozantinib shows potential as an adjunct therapy for patients with ABCG2-mediated drug-resistant cancers.
Keywords:
ABC transporterBreast cancer resistant proteinCabozantinibMultidrug resistance

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