Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1.
Specific tyrosine kinase inhibitors (TKIs) are rapidly developing clinical tools applied for the inhibition of malignant cell growth and metastasis formation. Most of these newly developed TKI molecules are hydrophobic, thus rapidly penetrate the cell membranes to reach intracellular targets. However, a large number of tumor cells overexpress multidrug transporter membrane proteins, which efficiently extrude hydrophobic drugs and thus may prevent the therapeutic action of TKIs. In the present work, we demonstrate that the most abundant and effective cancer multidrug transporters, MDR1 and MRP1, directly interact with several TKIs under drug development or already in clinical trials. This interaction with the transporters does not directly correlate with the hydrophobicity or molecular structure of TKIs, and shows a large variability in transporter selectivity and affinity. We suggest that performing enzyme- and cell-based multidrug transporter interaction tests for TKIs may greatly facilitate drug development, and allow the prediction of clinical TKI resistance based on this mechanism. Moreover, diagnostics for the expression of specific multidrug transporters in the malignant cells, combined with information on the interactions of the drug transporter proteins with TKIs, should allow a highly effective, individualized clinical treatment for cancer patients.
Hegedus
Tamás
T
National Institute of Haematology and Immunology, Membrane Research Group of the Hungarian Academy of Sciences, Daróczi u. 24, Budapest, Hungary.
Orfi
László
L
Seprodi
Attila
A
Váradi
András
A
Sarkadi
Balázs
B
Kéri
György
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D000068877:Imatinib Mesylate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010879:Piperazines; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D011994:Recombinant Proteins; C421109:multidrug resistance-associated protein 1