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Apoptosis of metastatic prostate cancer cells by a combination of cyclin-dependent kinase and AKT inhibitors.

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.
AuthorsSubhra Mohapatra, Baoky Chu, Xiuhua Zhao, Julie Djeu, Jin Q Cheng, W Jackson Pledger
JournalThe international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 41 Issue 3 Pg. 595-602 (Mar 2009) ISSN: 1878-5875 [Electronic] Netherlands
PMID18708158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • API 2
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Chromones
  • Membrane Proteins
  • Morpholines
  • Nucleic Acid Synthesis Inhibitors
  • Proto-Oncogene Proteins
  • Purines
  • RNA, Small Interfering
  • X-Linked Inhibitor of Apoptosis Protein
  • Roscovitine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Dichlororibofuranosylbenzimidazole
  • DNA
  • Proto-Oncogene Proteins c-akt
  • Cyclin-Dependent Kinase 9
  • Cyclin-Dependent Kinases
  • Caspase 9
  • Chlorpropamide
Topics
  • Apoptosis (drug effects)
  • Apoptosis Regulatory Proteins (genetics, metabolism)
  • Bcl-2-Like Protein 11
  • Caspase 9 (genetics, metabolism)
  • Cell Line, Tumor
  • Chlorpropamide (analogs & derivatives, pharmacology)
  • Chromones (pharmacology)
  • Cyclin-Dependent Kinase 9 (genetics, metabolism)
  • Cyclin-Dependent Kinases (antagonists & inhibitors)
  • DNA (biosynthesis)
  • Dichlororibofuranosylbenzimidazole (pharmacology)
  • Drug Synergism
  • Humans
  • Male
  • Membrane Proteins (genetics, metabolism)
  • Mitochondria (drug effects, metabolism, pathology)
  • Morpholines (pharmacology)
  • Nucleic Acid Synthesis Inhibitors (pharmacology)
  • Prostatic Neoplasms (drug therapy, metabolism, pathology)
  • Proto-Oncogene Proteins (genetics, metabolism)
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
  • Purines (pharmacology)
  • RNA, Small Interfering (genetics)
  • Roscovitine
  • X-Linked Inhibitor of Apoptosis Protein (metabolism)

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