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Microtubule-targeting anticancer drug eribulin induces drug efflux transporter P-glycoprotein

Tomohiro Nabekura1, Tatsuya Kawasaki1, Misuzu Jimura1

  • 1Department of Pharmaceutics, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.

Biochemistry and Biophysics Reports
|January 30, 2020
PubMed

Insights

The anticancer drug eribulin increases P-glycoprotein (encoded by MDR1) in intestinal and breast cancer cells. This may affect how well other cancer drugs work.

Area of Science:

  • Pharmacology and Molecular Biology
  • Cancer Therapeutics

Background:

  • P-glycoprotein, encoded by the MDR1 gene, is a crucial drug efflux transporter.
  • Microtubule-targeting anticancer drugs are widely used, but their impact on P-glycoprotein expression is not fully understood.

Purpose of the Study:

  • To investigate the effects of microtubule-targeting anticancer drugs (paclitaxel, cabazitaxel, eribulin) on P-glycoprotein expression.
  • To explore the roles of nuclear receptors pregnane X receptor (PXR) and co-repressor SMRT in regulating MDR1 activation by these drugs.

Main Methods:

  • Assessed MDR1 promoter activity in human intestinal LS174T cells treated with varying drug concentrations.
  • Examined the influence of PXR and SMRT gene expression on MDR1 activation.
  • Measured P-glycoprotein mRNA and protein levels, and cellular uptake of P-glycoprotein substrates (rhodamine 123, calcein-AM) in treated cells.

Main Results:

  • Paclitaxel and eribulin induced MDR1 promoter activity in a concentration-dependent manner in LS174T cells; cabazitaxel had minimal effect.
  • PXR overexpression enhanced paclitaxel- and eribulin-induced MDR1 activation, while SMRT repressed it.
  • Eribulin increased P-glycoprotein expression and decreased substrate uptake in LS174T cells, and also increased MDR1 activity in MCF7 breast cancer cells.

Conclusions:

  • The microtubule-targeting drug eribulin induces the drug efflux transporter P-glycoprotein via PXR in intestinal and breast cancer cells.
  • This induction of P-glycoprotein by eribulin may influence the efficacy of co-administered anticancer drugs.
Keywords:
Drug transporterDrug–drug interactionEribulin mesylateInductionP-glycoproteinPXR, pregnane X receptorRXRα, retinoid X receptor αSMRT, silencing mediator for retinoid and thyroid receptors

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