Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: Substrates, chemosensitizers or inducers of acquired multidrug resistance?

Anna Brózik, Csilla Hegedüs, Zsuzsa Erdei, Tamás Hegedüs, Csilla Özvegy-Laczka, Gergely Szakács, Balázs Sarkadi

Research output: Contribution to journalReview article

85 Citations (Scopus)

Abstract

Introduction: Anticancer tyrosine kinase inhibitors (TKIs) are small molecule hydrophobic compounds designed to arrest aberrant signaling pathways in malignant cells. Multidrug resistance (MDR) ATP binding cassette (ABC) transporters have recently been recognized as important determinants of the general ADME-Tox (absorption, distribution, metabolism, excretion, toxicity) properties of small molecule TKIs, as well as key factors of resistance against targeted anticancer therapeutics. Areas covered: The article summarizes MDR-related ABC transporter interactions with imatinib, nilotinib, dasatinib, gefitinib, erlotinib, lapatinib, sunitinib and sorafenib, including in vitro and in vivo observations. An array of methods developed to study such interactions is presented. Transporter-TKI interactions relevant to the ADME-Tox properties of TKI drugs, primary or acquired cancer TKI resistance, and drug-drug interactions are also reviewed. Expert opinion: Based on the concept presented in this review, TKI anticancer drugs are considered as compounds recognized by the cellular mechanisms handling xenobiotics. Accordingly, novel anticancer therapies should equally focus on the effectiveness of target inhibition and exploration of potential interactions of the designed molecules by membrane transporters. Thus, targeted hydrophobic small molecule compounds should also be screened to evade xenobiotic-sensing cellular mechanisms.

Original languageEnglish
Pages (from-to)623-642
Number of pages20
JournalExpert Opinion on Drug Metabolism and Toxicology
Volume7
Issue number5
DOIs
Publication statusPublished - May 1 2011

Keywords

  • ADME-Tox properties
  • chemoimmunity network
  • chemosensitization by transporter inhibition
  • induced xenobiotics resistance
  • multidrug transporters
  • tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint Dive into the research topics of 'Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: Substrates, chemosensitizers or inducers of acquired multidrug resistance?'. Together they form a unique fingerprint.

  • Cite this