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Updated: Jun 3, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib

Yoshihiko Shibayama1, Kou Nakano, Hiroshi Maeda

  • 1Education Research Center for Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan.

Biological & Pharmaceutical Bulletin
|March 5, 2011
PubMed

Insights

Sorafenib resistance in renal cell carcinoma may be linked to multidrug resistance protein 2 (MRP2). MRP2 affects sorafenib concentration, but not sunitinib, suggesting MRP2 implicates sorafenib drug resistance.

Area of Science:

  • Pharmacology
  • Oncology
  • Molecular Biology

Background:

  • Sorafenib and sunitinib are small molecule tyrosine kinase inhibitors improving outcomes in advanced renal cell carcinoma.
  • Multidrug resistance protein 2 (MRP2) is implicated in drug efflux and resistance.
  • Understanding drug transporter roles is crucial for optimizing cancer therapy.

Purpose of the Study:

  • To investigate the role of MRP2 in the cellular disposition and efficacy of sorafenib and sunitinib.
  • To determine if sorafenib or sunitinib are substrates of MRP2.
  • To explore the potential of MRP2 in mediating drug resistance to these tyrosine kinase inhibitors.

Main Methods:

  • Cell-based assays using MRP2-transfected and control cell lines.
  • Measurement of 50% inhibitory concentration (IC50) for cell growth.
  • Quantification of intracellular drug accumulation.
  • Treatment of cells with sorafenib and sunitinib.

Main Results:

  • Sorafenib's IC50 significantly increased 6.4-fold in MRP2-transfected cells compared to controls.
  • Intracellular sorafenib concentration was reduced to 74% in MRP2-transfected cells after 3 hours.
  • Sunitinib showed no significant alteration in IC50 or intracellular accumulation in MRP2-transfected cells.

Conclusions:

  • Sorafenib is identified as a substrate for the MRP2 transporter.
  • MRP2-mediated efflux likely contributes to reduced intracellular concentrations of sorafenib.
  • These findings suggest that MRP2 plays a role in conferring drug resistance to sorafenib in renal cell carcinoma.

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