title: Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance?
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hungarian Academy of Sciences and Semmelweis University, Membrane Biology, Budapest, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Brózik
authors.forename: Csilla
authors.initials: C
authors.lastname: Hegedüs
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Erdei
authors.forename: Tamás
authors.initials: T
authors.lastname: Hegedus
authors.forename: Csilla
authors.initials: C
authors.lastname: Özvegy-Laczka
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
authors.forename: Balázs
authors.initials: B
authors.lastname: Sarkadi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases