Bortezomib and sphingosine kinase inhibitor interact synergistically to induces apoptosis in BCR/ABl(+) cells sensitive and resistant to STI571 through down-regulation Mcl-1

作者：Li, Qing-Fang; Yan, Jun; Zhang, Kai; Yang, Yue-Feng; Xiao, Feng-Jun; Wu, Chu-Tse; Wang, Hua^*; Wang, Li-Sheng

来源：Biochemical and Biophysical Research Communications, 2011, 405(1): 31-36.

DOI：10.1016/j.bbrc.2010.12.111

• Bortezomib
• Sphingosine kinase inhibitor
• Apoptosis
• CML cells
• Mcl-1

Interactions between the proteasome inhibitor, bortezomib, and the sphingosine kinase (SPK1) inhibitor, SKI, were examined in BCR/ABL human leukemia cells. Coexposure of K562 or chronic myeloid leukemia (CML) cells from patients to subtoxic concentrations of SKI (10 mu M) and bortezomib (100 nM) resulted in a synergistic increase in caspase-3 cleavage and apoptosis. These events were associated with the downregulation of BCR-ABL and Mcl-1, and a marked reduction in SPK1 expression. In imatinib mesylate-resistant K562 cells that displayed decreased BCR-ABL expression, bortezomib/SKI treatment markedly increased apoptosis and inhibited colony-formation in association with the downregulation of Mcl-1. Finally, the bortezomib/SKI regimen also potently induced the downregulation of BCR/ABL and Mcl-1 in human leukemia cells. Collectively, these findings suggest that combining SKI and bortezomib may represent a novel strategy in leukemia, including apoptosis-resistant BCR-ABL(+) hematologic malignancies.

• 出版日期2011-2-4
• 单位中国人民解放军总医院; 北京中医药大学