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Flavopiridol Potentiates STI571-induced Mitochondrial Damage and Apoptosis in BCR-ABL-positive Human Leukemia Cells¹

Departments of Medicine [C. Y., G. K., S. G.], Radiation Oncology [P. D.], Pharmacology [S. G.], and Biochemistry [S. G.], Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

Purpose: The goal of this study was to characterize interactions between the Bcr/Abl kinase inhibitor STI571 and the cyclin-dependent kinase inhibitor flavopiridol in Bcr/Abl⁺ human leukemia cells.

Experimental Design: K562 leukemia cells were exposed to STI571 ± flavopiridol for 24 or 48 h, after which mitochondrial damage, caspase activation, expression/activation of signaling and cell cycle regulatory proteins, and apoptosis were assessed.

Results: In K562 cells, coadministration of marginally toxic concentrations of STI571 (200 nM) and flavopiridol (150 nM) for 48 h resulted in a marked increase in mitochondrial damage (e.g., cytochrome c release), activation of caspase-3, caspase-8, and Bid, and apoptosis. Similar interactions were observed in Bcr/Abl⁺ LAMA-84 cells but not in leukemic cells that fail to express Bcr/Abl (e.g., HL-60, U937, Jurkat). STI571/flavopiridol-mediated apoptosis was associated with the caspase-independent down-regulation of Bcl-x_L and Mcl-1, activation of extracellular signal-regulated kinase and c-Jun NH₂-terminal kinase, and the caspase-dependent release of Smac/DIABLO and loss of _m. Coadministration of flavopiridol and STI571 did not result in changes in levels of expression of Bcl-2, phopho-Stat5, phospho-p34^cdc2, or Bcr/Abl. Finally, STI571/flavopiridol effectively induced apoptosis in STI571-resistant K562 cells displaying amplification of the Bcr/Abl protein.

Conclusions: Together, these findings indicate that the cyclin-dependent kinase inhibitor flavopiridol induces multiple perturbations in signaling pathways in STI571-treated Bcr/Abl⁺ human leukemia cells that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that simultaneous disruption of survival signaling and cell cycle regulatory pathways may represent an effective strategy in Bcr/Abl⁺ malignancies.

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