The tyrosine kinase inhibitors imatinib and AG957 reverse multidrug resistance in a chronic myelogenous leukemia cell line.
The K562 cell line derived from a chronic myelogenous leukemia (CML) patient exhibits ATP-dependent exclusion of the multidrug resistance (MDR)-type drugs. The protein tyrosine kinases inhibitors, imatinib mesylate and AG957 allowed for increased doxorubicin and calcein-AM accumulation in these cells. Maximal modulation was achieved at 3 and 10 microM imatinib and AG957, respectively. This imatinib concentration is comparable to the plasma steady state levels observed in patients. Although the increase in cellular accumulation followed a time course similar to apoptotic manifestations induced by these drugs, the two phenomena seem independent. There was no correlation between the levels of MDR reversal and apoptosis in clones derived from the K562 cell line. Moreover, whereas protein kinase inhibitors induced apoptosis in only a fraction of the cells, the MDR reversal occurred in all of them. Inhibition of apoptosis by a non-specific inhibitor of caspases was not associated with MDR reversal. The consequence of these findings is that combination of tyrosine kinase inhibitors with antileukemic drugs is likely to have the added beneficial effect of allowing MDR-type drugs better access to cells.
Yeheskely-Hayon
Daniella
D
Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Regev
Ronit
R
Eytan
Gera D
GD
Dann
Eldad J
EJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects / Q000473:pathology*; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D020032:Tyrphostins; C104965:tyrphostin AG957; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl