[Arsenic trioxide inhibits cell growth in imatinib-resistant bcr-abl mutant cell lines in vitro].
OBJECTIVE
To explore the effect of arsenic trioxide (As2O3) on the growth inhibition of imatinib (IM)-resistant bcr-abl mutant cell lines in vitro.


METHODS
Cell growth of one IM-sensitive cell line, 32Dp210 and 15 IM-resistant cell lines including T315I and other 14 bcr-abl mutants were detected by MTT assay after treatment with IM and As2O3. The cell lines with 5 frequently observed mutants in CML patients were analyzed for apoptosis by flow cytometry with Annexin V and PI staining as well as the expression of bcr-abl fusion protein, phosphorylated CRKL protein and apoptosis-related proteins by Western blot.


RESULTS
The fifty percent inhibition concentration (IC50) values of As2O3 for 15 IM-resistant cell lines were 2.6-5.3 fold lower than that for IM-sensitive cell line. For the 5 bcr-abl mutants frequently happened in CML patients, As2O3 significantly inhibited the expression of bcr-abl fusion protein and phosphorylated CRKL and induced apoptosis in a dose-dependent manner as compared with that for 32Dp210. Coincidently, the cell apoptosis was induced through caspase-3, 8 and 9 pathways.


CONCLUSIONS
As2O3 remarkably inhibits cell growth and induces apoptosis of IM-resistant bcr-abl mutant cell lines in vitro, suggesting that it might be a potential therapeutic agent for IM-resistant CML patients.
Lu
Run-Zhang
RZ
Harbin Institute of Hematology & Oncology, Harbin 150010, China.
Qiu
Lin
L
Wang
Xiao-Dan
XD
Li
Xiao-Feng
XF
Chen
Li-Jun
LJ
Wang
Xiu-Li
XL
Zhang
Bo-Long
BL
Ma
Jun
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D001152:Arsenicals; D001549:Benzamides; C082869:CRKL protein; D009687:Nuclear Proteins; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000077237:Arsenic Trioxide