HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Caspase-mediated apoptosis and caspase-independent cell death induced by irofulven in prostate cancer cells.

Abstract
Irofulven (hydroxymethylacylfulvene) is a novel antitumor drug, which acts by alkylating cellular macromolecular targets. The drug is a potent inducer of apoptosis in various types of tumor cells, whereas it is nonapoptotic in normal cells. This study defined molecular responses to irofulven involving mitochondrial dysfunction and leading to death of prostate tumor LNCaP-Pro5 cells. Irofulven caused early (2-5 hours) translocation of the proapoptotic Bax from cytosol to mitochondria followed by the dissipation of mitochondrial membrane potential and cytochrome c release at 4 to 12 hours. These effects preceded caspase activation and during the first 6 hours were not affected by caspase inhibitors. Processing of caspase-9 initiated the caspase cascade at approximately 6 hours and progressed over time. The activation of the caspase cascade provided a positive feedback loop that enhanced Bcl-2-independent translocation and cytochrome c release. General and specific caspase inhibitors abrogated irofulven-induced apoptotic DNA fragmentation with the following order of potency: pan-caspase > or = caspase-9 > caspase-8/6 > caspase-2 > caspase-3/7 > caspase-1/4. Abrogation of caspase-mediated DNA fragmentation failed to salvage irofulven-treated cells from growth inhibition and loss of viability, demonstrating a substantial contribution of a caspase-independent cell death. Monobromobimane, an inhibitor of alternative caspase-independent apoptotic pathway that is mediated by mitochondrial permeability transition, antagonized both apoptosis, measured as phosphatidylserine externalization, and cytotoxicity of irofulven. Collectively, the results indicate that irofulven-induced signaling is integrated at the level of mitochondrial dysfunction. The induction of both caspase-dependent and caspase-independent death pathways is consistent with pleiotropic effects of irofulven, which include targeting of cellular DNA and proteins.
AuthorsHuiyun Liang, Richard A Salinas, Belinda Z Leal, Teresa Kosakowska-Cholody, Christopher J Michejda, Stephen J Waters, Terence S Herman, Jan M Woynarowski, Barbara A Woynarowska
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 11 Pg. 1385-96 (Nov 2004) ISSN: 1535-7163 [Print] United States
PMID15542777 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • BAX protein, human
  • Bridged Bicyclo Compounds
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Sesquiterpenes
  • bcl-2-Associated X Protein
  • irofulven
  • Cytochromes c
  • Caspases
  • monobromobimane
Topics
  • Apoptosis (drug effects)
  • Bridged Bicyclo Compounds (pharmacology)
  • Caspases (metabolism)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cytochromes c (metabolism)
  • DNA Fragmentation (drug effects)
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Humans
  • Male
  • Mitochondria (drug effects, metabolism)
  • Molecular Structure
  • Prostatic Neoplasms (enzymology, metabolism, pathology)
  • Protein Transport (drug effects)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Sesquiterpenes (chemistry, pharmacology)
  • Signal Transduction (drug effects)
  • bcl-2-Associated X Protein

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: