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Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects

C Hegedus1, C Ozvegy-Laczka, A Apáti

  • 1Membrane Research Group of the Hungarian Academy of Sciences, National Blood Center and Semmelweis University, Budapest, Hungary.

British Journal of Pharmacology
|September 30, 2009
PubMed
Abstract

Insights

Second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib are substrates of ABCG2, conferring cancer cell resistance. Understanding these multidrug resistance transporter interactions is key for targeted cancer therapy.

Area of Science:

  • Pharmacology
  • Oncology
  • Molecular Biology

Background:

  • Multidrug resistance-associated ABC transporters (MDR-ABC) impact cancer treatment efficacy.
  • First-generation TKIs like imatinib interact with ABCB1 and ABCG2 transporters.
  • Novel targeted agents may face altered pharmacokinetics due to MDR-ABC interactions.

Purpose of the Study:

  • Investigate interactions between ABCB1, ABCG2, and second-generation Bcr-Abl TKIs: nilotinib, dasatinib, and bosutinib.
  • Determine the functional impact of these interactions on TKI efficacy in cancer cells.
  • Assess the potential of MDR-ABC transporters to confer resistance to these novel TKIs.

Main Methods:

  • Screened MDR-ABC transporter function using membrane- and cell-based assays (K562 cells).
  • Measured cytotoxicity and intracellular TKI concentrations (HPLC-MS).
  • Analyzed Bcr-Abl phosphorylation and transporter ATPase activity.

Main Results:

  • Nilotinib and dasatinib are high-affinity ABCG2 substrates, mediating cancer cell resistance.
  • ABCB1 conferred resistance to dasatinib but not nilotinib.
  • Bosutinib was not a substrate for either ABCB1 or ABCG2; however, all TKIs inhibited both transporters at higher concentrations.

Conclusions:

  • In vitro assays provide preclinical insights into novel TKI applicability in multidrug-resistant cancers.
  • Understanding TKI-MDR-ABC transporter interactions aids in predicting pharmacokinetics and toxicities.
  • Specific transporter interactions influence the effectiveness of targeted cancer therapies.

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