International journal of laboratory hematology · 2010
An investigation of reversal of imatinib resistance in the Bcr-Abl positive imatinib-resistant cell line K562r by dasatinib, nilotinib, rapamycin and bortezomib.
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Xing H, Liu T, Meng W, Gong Y
Аннотация
INTRODUCTION: We investigated the second-generation tyrosine kinase inhibitors, dasatinib and nilotinib, for their potential to overcome resistance in the imatinib-resistant K562 cell line, and evaluated whether rapamycin, an mammalian target of rapamycin (mTOR) inhibitor, and bortezomib, a proteasome inhibitor, could increase imatinib sensitivity in resistant cell lines.
METHODS: Cell lines, including K562 (chronic myeloid leukaemia in blast crisis) and K562r (imatinib-resistant K562), were exposed to dasatinib, nilotinib, rapamycin, bortezomib, and rapamycin plus imatinib. Cell proliferation was measured by 3-[4, 5-dimethylthia-zol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay and mTOR signaling pathways were assessed by Western blotting.
RESULTS: Dasatinib, nilotinib, and bortezomib inhibited proliferation of K562 and K562r cell lines at nm concentrations. Resistance of K562r due to duplication of autophosphorylation of wild-type Bcr-Abl was not overcome by dasatinib and nilotinib, but was sensitive to bortezomib. Rapamycin partially inhibited proliferation of K562 and K562r cell lines. Rapamycin plus imatinib did not have a more inhibitory effect on the proliferation of K562 and K562r cell lines.
CONCLUSION: K562r due to duplication of autophosphorylation of wild-type Bcr-Abl induced by imatinib was still partially resistant to dasatinib and nilotinib, but this was overcome by incremental dosing. Rapamycin did not enhance imatinib sensitivity. The blockade of the ubiquitin-proteasome pathway could be effective in overcoming resistance in the K562r imatinib-resistant cell line.
METHODS: Cell lines, including K562 (chronic myeloid leukaemia in blast crisis) and K562r (imatinib-resistant K562), were exposed to dasatinib, nilotinib, rapamycin, bortezomib, and rapamycin plus imatinib. Cell proliferation was measured by 3-[4, 5-dimethylthia-zol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay and mTOR signaling pathways were assessed by Western blotting.
RESULTS: Dasatinib, nilotinib, and bortezomib inhibited proliferation of K562 and K562r cell lines at nm concentrations. Resistance of K562r due to duplication of autophosphorylation of wild-type Bcr-Abl was not overcome by dasatinib and nilotinib, but was sensitive to bortezomib. Rapamycin partially inhibited proliferation of K562 and K562r cell lines. Rapamycin plus imatinib did not have a more inhibitory effect on the proliferation of K562 and K562r cell lines.
CONCLUSION: K562r due to duplication of autophosphorylation of wild-type Bcr-Abl induced by imatinib was still partially resistant to dasatinib and nilotinib, but this was overcome by incremental dosing. Rapamycin did not enhance imatinib sensitivity. The blockade of the ubiquitin-proteasome pathway could be effective in overcoming resistance in the K562r imatinib-resistant cell line.