Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

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Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia

cells with impaired oxygen consumption and mobilization of intracellular

calcium.

Syed-Rehan A Hussain, M Lucas, Amy J , S Lin, Alan P

Bakaletz, Vinh X Dang, Serge Viatchenko-Karpinski, Amy S Ruppert, C Byrd,

Periannan Kuppusamy, Elliott D Crouser, and R Grever

Blood, January 11, 2008

Department of Internal Medicine, Ohio State University, Columbus, OH, United

States

Effective administration of flavopiridol in advanced-stage chronic lymphocytic

leukemia (CLL) is often associated with early biochemical evidence of tumor cell

lysis. Previous work using other cell types showed that flavopiridol impacts

mitochondria, and in CLL cells flavopiridol down-regulates the mitochondrial

protein Mcl-1. We therefore investigated mitochondrial structure and function in

flavopiridol-treated CLL patient cells and in the lymphoblastic cell line 697

using concentrations and times at which tumor lysis is observed in treated

patients. Mitochondrial membrane depolarization was detected in

flavopiridol-treated CLL cells by six hours, well before the onset of cell

death. Flavopiridol-induced mitochondrial depolarization was not blocked by

caspase inhibitors or by the calcium chelator EGTA, but was reduced by Bcl-2

overexpression. Intracellular calcium mobilization was noted at early timepoints

using fluorescence microscopy. Furthermore, electron paramagnetic resonance

oximetry showed a gradual but significant reduction in cellular oxygen

consumption rate by six hours, corresponding with ultrastructural mitochondrial

damage detected by electron microscopy. These observations suggest that in CLL

and 697 cells, flavopiridol mediates its cytotoxic effects via induction of the

mitochondrial permeability transition and changes in intracellular calcium.

PMID: 18192508