Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells.
STI571, an Abl-specific tyrosine kinase inhibitor, selectively kills Bcr-Abl-containing cells in vitro and in vivo. However, some chronic myelogenous leukemia (CML) cell lines are resistant to STI571. We evaluated whether STI571 interacts with P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1), and examined the effect of agents that reverse multidrug resistance (MDR) on the resistance to SI571 in MDR cells. STI571 inhibited the [(125)I]azidoagosterol A-photolabeling of P-gp, but not that of MRP1. K562/MDR cells that overexpress P-gp were 3.67 times more resistant to STI571 than the parental Philadelphia-chromosome-positive (Ph +) CML K562 cells, and this resistance was most effectively reversed by cepharanthine among the tested reversing agents. The concentration of STI571 required to completely inhibit tyrosine phosphorylation in K562/MDR cells was about 3 times higher than that in K562 cells, and cepharanthine abolished the difference. In KB-G2 cells that overexpress P-gp, but not Bcr-Abl, 2.5 micro M STI571 partly reversed the resistance to vincristine (VCR), paclitaxel, etoposide (VP-16) and actinomycin D (ACD) but not to Adriamycin (ADM) or colchicine. STI571 increased the accumulation of VCR, but not that of ADM in KB-G2 cells. STI571 did not reverse resistance to any agent in KB/MRP cells that overexpress MRP1. These findings suggest that STI571 is a substrate for P-gp, but is less efficiently transported by P-gp than VCR, and STI571 is not a substrate for MRP1. Among the tested reversing agents that interact with P-gp, cepharanthine was the most effective agent for the reversal of the resistance to STI571 in K562/MDR cells. Furthermore, STI571 itself was a potent reversing agent for MDR in P-gp-expressing KB-G2 cells.
Mukai
Motoi
M
Department of Cancer Chemotherapy, Institute for Cancer Research, Kagoshima University, Kagoshima 890-8520, Japan.
Che
Xiao-Fang
XF
Furukawa
Tatsuhiko
T
Sumizawa
Tomoyuki
T
Aoki
Shunji
S
Ren
Xiao-Qin
XQ
Haraguchi
Misako
M
Sugimoto
Yoshikazu
Y
Kobayashi
Motomasa
M
Takamatsu
Hideo
H
Akiyama
Shin-Ichi
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001549:Benzamides; D002462:Cell Membrane; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007624:KB Cells / Q000187:drug effects / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D015289:Leukotrienes / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019920:Photoaffinity Labels; D010879:Piperazines / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D014443:Tyrosine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D015289:Leukotrienes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019920:Photoaffinity Labels; D010879:Piperazines; D011743:Pyrimidines; D014443:Tyrosine; C421109:multidrug resistance-associated protein 1