High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter.
Tyrosine kinase inhibitors (TKIs) are promising new agents for specific inhibition of malignant cell growth and metastasis formation. Because most of the TKIs have to reach an intracellular target, specific membrane transporters may significantly modulate their effectiveness. In addition, the hydrophobic TKIs may interact with so-called multidrug transporters and thus alter the cellular distribution of unrelated pharmacological agents. In the present work, we show that certain TKIs, already in the clinical phase of drug development, directly interact with the ABCG2 multidrug transporter protein with a high affinity. We found that in several in vitro assay systems, STI-571 (Gleevec; imatinib mesylate), ZD1839 (Iressa; gefitinib), and N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (EKI-785) interacted with ABCG2 at submicromolar concentrations, whereas other multidrug transporters, human multidrug resistance protein (P-glycoprotein, ABCB1) and human multidrug resistance protein 1 (ABCC1), showed much lower reactivity toward these agents. Low concentrations of the TKIs examined selectively modulated ABCG2-ATPase activity, inhibited ABCG2-dependent active drug extrusion, and significantly affected drug resistance patterns in cells expressing ABCG2. Our results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the clinical treatment of cancer patients. These data also raise the possibility that an extrusion of TKIs by multidrug transporters, e.g., ABCG2, may be involved in tumor cell TKI resistance.
Ozvegy-Laczka
Csilla
C
National Medical Center, Institute of Hematology and Immunology, Membrane Research Group of the Hungarian Academy of Sciences, Budapest, Hungary.
Hegedus
Tamás
T
Várady
György
G
Ujhelly
Olga
O
Schuetz
John D
JD
Váradi
András
A
Kéri
György
G
Orfi
László
L
Német
Katalin
K
Sarkadi
Balázs
B
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007313:Insecta / Q000166:cytology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D000251:Adenosine Triphosphatases