Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties.
OBJECTIVE
ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity.


METHODS
MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity.


RESULTS
Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters.


CONCLUSIONS
A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.
Hegedus
C
C
Membrane Research Group of the Hungarian Academy of Sciences, National Blood Center and Semmelweis University, Budapest, Hungary.
Ozvegy-Laczka
C
C
Apáti
A
A
Magócsi
M
M
Német
K
K
Orfi
L
L
Kéri
G
G
Katona
M
M
Takáts
Z
Z
Váradi
A
A
Szakács
G
G
Sarkadi
B
B
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003524:Cyclosporins / Q000494:pharmacology; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020014:K562 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy; D009570:Nitriles / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D013379:Substrate Specificity; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D003524:Cyclosporins; D007211:Indoles; D009363:Neoplasm Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; C010522:tryptoquivaline; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; C070272:valspodar; D000069439:Dasatinib