Enhancement of depsipeptide-mediated apoptosis of lung or esophageal cancer cells by flavopiridol: Activation of the mitochondria-dependent death-signaling pathway

Objective: Treating cancer cells with depsipeptide, a novel antitumor agent currently in a phase II clinical trial, causes potent upregulation of p21/WAF1 expression and cell arrest at G1 and G2 checkpoints. p21/WAF1 upregulation, however, impedes the ability of depsipeptide to induce significant ap...

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Published in:The Journal of thoracic and cardiovascular surgery 2003-05, Vol.125 (5), p.1132-1142
Main Authors: Nguyen, Dao M., Schrump, William D., Tsai, Wilson S., Chen, Aaron, Stewart, John H., Steiner, Federico, Schrump, David S.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - pathology
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases - antagonists & inhibitors
Cyclins - drug effects
Depsipeptides
Drug Synergism
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Esophageal Neoplasms - drug therapy
Esophageal Neoplasms - pathology
Flavonoids - pharmacology
Flavonoids - therapeutic use
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Mitochondria - drug effects
Peptides, Cyclic - pharmacology
Peptides, Cyclic - therapeutic use
Piperidines - pharmacology
Piperidines - therapeutic use
Tumor Cells, Cultured - drug effects
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Summary:Objective: Treating cancer cells with depsipeptide, a novel antitumor agent currently in a phase II clinical trial, causes potent upregulation of p21/WAF1 expression and cell arrest at G1 and G2 checkpoints. p21/WAF1 upregulation, however, impedes the ability of depsipeptide to induce significant apoptosis. This study was designed to determine whether flavopiridol, a synthetic cyclin-dependent kinase inhibitor known to inhibit p21 expression in tumor cells, could enhance depsipeptide-mediated apoptosis in cultured lung and esophageal cancer cells. Methods: Lung or esophageal cancer cells were exposed to depsipeptide, flavopiridol, or a combination of depsipeptide and flavopiridol. Cytotoxicity and apoptosis were quantitated by means of (4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-based assays, respectively. Cytosolic cytochrome c levels, caspase 9 activity, mitochondrial membrane depolarization, and dependence of apoptosis on caspase 9 in treated cells were studied to determine the role of the mitochondria in mediating apoptosis induced by this drug combination. Results: Flavopiridol completely abolished depsipeptide-mediated dose-dependent upregulation of p21/WAF1 expression. Combining flavopiridol with depsipeptide resulted in a 3- to 8-fold reduction of depsipeptide inhibitory concentration of 50% values that was closely paralleled by synergistic enhancement of apoptosis (4- to 10-fold higher than levels of cell death induced by either drug alone) in all cancer cell lines. The essential role of mitochondria in mediating cell death was indicated by robust translocation of cytochrome c from the mitochondria into the cytosol, 2.5- to 5-fold activation of caspase 9, severe disruption of mitochondrial inner membrane potential, and complete inhibition of apoptosis by the selective caspase 9 inhibitor. More important, this drug combination was not toxic to primary normal epithelial cells derived from the airway or skin. Conclusion: The depsipeptide plus flavopiridol combination exhibits powerful and selective cytocidal activity against cancer but not normal cells. Apoptosis induced by this combination is mediated by the mitochondria-dependent death pathway. J Thorac Cardiovasc Surg 2003;125:988-91
ISSN:0022-5223
1097-685X
DOI:10.1067/mtc.2003.180