Bortezomib and Flavopiridol Interact Synergistically to Induce Apoptosis in Bcr/abl+ Cells Sensitive and Resistant to Sti571

Interactions between the CDK (cyclin-dependent kinase) inhibitor Flavopiridol and the proteasome inhibitor Bortezomib were examined in Bcr/Abl human leukemia cells. Co-exposure of K562 or LAMA84 cells to subtoxic concentration of Flavopiridol (150-200nM) and Bortezomib (5-8nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in NF-κB/DNA binding activity, enhanced phosphorylation of SEK1/MKK4, JNK, and p38 MAPK, down-regulation of Bcr/Abl, and a marked reduction in STAT3 and STAT5 activity. In imatinib-resistant K562 cells displaying increased Bcr/Abl expression, Bortezomib/Flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and Bcl-xL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl, but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/Bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of Flavopiridol to promote Bortezomib-mediated Bcr/Abl downregulation and apoptosis was mimicked by the PTEFb inhibitor DRB. Finally, the Bortezomib/Flavopiridol regimen also potently induced apoptosis in Bcr/Abl human leukemia cells. Collectively, these findings suggest that a strategy combining Flavopiridol and Bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies. For personal use only. on April 14, 2017. by guest www.bloodjournal.org From