Abstract
Effective treatments for advanced prostate cancer are much needed. Toward this goal, we show apoptosis and impaired long-term survival of androgen-independent prostate cancer cells (PC3 and PC3 derivatives) co-treated with the cyclin-dependent kinase (CDK) inhibitor roscovitine and an AKT inhibitor (LY294002 or API-2). Apoptosis of PC3 cells by the drug combination required caspase-9 but not caspase-8 activity and thus is mitochondria-dependent. Roscovitine reduced amounts of the caspase inhibitor XIAP, and API-2 increased amounts of the BH3-only protein Bim. PC3 cells apoptosed when co-treated with API-2 and either cdk9 siRNA, dominant-negative cdk9, or the cdk9 inhibitor DRB; they did not apoptose when co-treated with API-2 and XIAP siRNA. Bax accumulated in mitochondria in response to API-2, whereas release of cytochrome c from mitochondria required both API-2 and roscovitine. We suggest that roscovitine elicits events that activate Bax once it translocates to mitochondria and that inactivation of cdk9 signals these events and the down-regulation of XIAP. Collectively, our data show apoptosis of prostate cancer cells by a drug combination and identify Bax activation as a basis of cooperation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Caspase 9 / genetics
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Caspase 9 / metabolism*
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Cell Line, Tumor
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Chlorpropamide / analogs & derivatives
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Chlorpropamide / pharmacology
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Chromones / pharmacology
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Cyclin-Dependent Kinase 9 / genetics
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Cyclin-Dependent Kinase 9 / metabolism*
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Cyclin-Dependent Kinases / antagonists & inhibitors
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DNA / biosynthesis
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Dichlororibofuranosylbenzimidazole / pharmacology
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Drug Synergism
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Humans
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitochondria / pathology
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Morpholines / pharmacology
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Purines / pharmacology
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RNA, Small Interfering / genetics
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Roscovitine
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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API 2
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Chromones
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Membrane Proteins
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Morpholines
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Nucleic Acid Synthesis Inhibitors
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Proto-Oncogene Proteins
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Purines
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RNA, Small Interfering
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X-Linked Inhibitor of Apoptosis Protein
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Roscovitine
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Dichlororibofuranosylbenzimidazole
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DNA
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Proto-Oncogene Proteins c-akt
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Cyclin-Dependent Kinase 9
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Cyclin-Dependent Kinases
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Caspase 9
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Chlorpropamide