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Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

Verena Schneider1, Selim Chaib1, Claudia Spanier1

  • 1Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.

The AAPS Journal
|December 2, 2017
PubMed

Insights

Sorafenib addition to platinum chemotherapy may reduce drug accumulation and DNA platination in sensitive cancer cells by downregulating key transporters. This interaction appears antagonistic, potentially explaining decreased survival in some clinical trials.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Platinum-based chemotherapy is a cornerstone for solid tumors.
  • Sorafenib, a multikinase inhibitor, has shown limited benefit when combined with platinum drugs in clinical trials.
  • Some studies report decreased survival with sorafenib and platinum combinations, particularly in ovarian and non-small cell lung cancers.

Purpose of the Study:

  • To investigate the cellular mechanisms underlying the interaction between platinum drugs and sorafenib.
  • To determine how sorafenib affects platinum accumulation and DNA platination in various cancer cell lines.

Main Methods:

  • Combination index analysis to characterize drug interactions.
  • Flameless atomic absorption spectrometry to quantify platinum accumulation.
  • Western blot to assess protein expression, including Na+,K+-ATPase and copper transporter 1 (CTR1).

Main Results:

  • Sorafenib downregulated Na+,K+-ATPase and CTR1 in platinum-sensitive ovarian (A2780) and lung (H520) cancer cells.
  • This downregulation led to reduced cisplatin and carboplatin accumulation and decreased DNA platination.
  • No similar effect was observed in platinum-resistant cell lines (A2780cis, H522) with lower transporter expression.
  • An antagonistic interaction was consistently found between sorafenib and platinum drugs.

Conclusions:

  • Sorafenib impairs platinum drug uptake by downregulating CTR1 and/or Na+,K+-ATPase.
  • Reduced DNA platination by platinum drugs is a consequence of this impaired uptake.
  • The observed antagonistic effect may explain the lack of clinical benefit and decreased survival in certain patient groups.
Keywords:
Na+,K+-ATPaseantagonismcopper transporter 1platinum accumulation

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