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Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette

Yan-Jun Mi1, Yong-Ju Liang, Hong-Bing Huang

  • 1State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.

Cancer Research
|September 30, 2010
PubMed

Insights

Apatinib enhances chemotherapy by overcoming multidrug resistance (MDR) mediated by P-glycoprotein (ABCB1) and breast cancer resistance protein (BCRP, ABCG2). It inhibits their function, increasing drug accumulation and efficacy in cancer cells and xenografts.

Area of Science:

  • Pharmacology and Molecular Biology
  • Cancer Research
  • Drug Resistance Mechanisms

Background:

  • Multidrug resistance (MDR) significantly limits the efficacy of antineoplastic drugs.
  • P-glycoprotein (ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are key efflux pumps contributing to MDR.
  • Apatinib is a targeted tyrosine kinase inhibitor investigated for cancer treatment.

Purpose of the Study:

  • To investigate the effect of apatinib on drug efflux pumps ABCB1 and ABCG2.
  • To determine if apatinib can reverse MDR mediated by ABCB1 and ABCG2.
  • To elucidate the mechanism by which apatinib affects MDR.

Main Methods:

  • Assessed apatinib's effect on the cytotoxicity of substrate drugs in cells overexpressing ABCB1 and ABCG2.
  • Measured intracellular accumulation of drugs (rhodamine 123, doxorubicin) in MDR cells.
  • Evaluated apatinib's impact on ABCB1/ABCG2 photoaffinity labeling, ATPase activity, protein/mRNA expression, and signaling pathways (AKT, ERK1/2).
  • Tested apatinib's efficacy in combination with paclitaxel in a xenograft model.

Main Results:

  • Apatinib significantly enhanced the cytotoxicity of ABCB1 and ABCG2 substrate drugs in overexpressing cells.
  • Apatinib increased intracellular drug accumulation and inhibited photoaffinity labeling of ABCB1 and ABCG2.
  • Apatinib stimulated ABCB1 and ABCG2 ATPase activity but did not alter their expression levels or AKT/ERK1/2 phosphorylation.
  • Apatinib potentiated paclitaxel's effect against ABCB1-resistant xenografts.

Conclusions:

  • Apatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function.
  • The mechanism does not involve altering ABCB1/ABCG2 expression or the AKT/ERK1/2 signaling pathways.
  • Apatinib shows potential for overcoming MDR and improving the efficacy of conventional antineoplastic drugs.

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