Apoptosis-inducing active components from Corbicula fluminea through activation of caspase-2 and production of reactive oxygen species in human leukemia HL-60 cells.

Abstract

The anti-cancer effects and possible mechanisms of the freshwater clam (Corbicula fluminea Muller) and its active compounds (FME) on cell viability in human leukemia HL-60 cells were investigated. This study demonstrated that FME was able to inhibit cell proliferation in a concentration- and time-dependent manner. Treatment with FME caused induction of caspase-2, caspase-3, caspase-6, caspase-8, and caspase-9 activity in a time-dependent manner, but not affect caspase-1 activity; it induced the proteolysis of DNA fragmentation factor (DFF-45) and poly(ADP-ribose) polymerase (PARP). Induction of cell death by FME was completely prevented by a pan-caspase inhibitor, Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and a caspase-2 inhibitor, Z-Val-Asp-Val-Ala-Asp-FMK (Z-VDVAD-FMK). Furthermore, treatment with FME caused a rapid loss of mitochondrial transmembrane potential, stimulation of generation of reactive oxygen species (ROS), release of mitochondrial cytochrome c into cytosol, and GSH depletion. Anti-oxidants such as N-acetylcysteine, catalase, superoxide dismutase, allopurinol, and pyrrolidine dithiocarbamate, but not diphenylene iodonium, significantly inhibited FME-induced cell death. In addition, the results showed that FME-induced apoptosis was accompanied by up-regulation of Bax and Bad, and down-regulation of Bcl-2 and Bcl-XL. Taken together, induction of apoptosis on HL-60 cells by FME was mainly associated with ROS production, GSH depletion, mitochondrial dysfunction, and caspase activation.

• Authors: Ying-Tang Huang, Yi-Hsuan Huang, Tzhy-Chyuan Hour, Bonnie Sun Pan, Yeuk-Chuen Liu, Min-Hsiung Pan
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 44 Issue 8 Pg. 1261-72 (Aug 2006) ISSN: 0278-6915 [Print] England
• PMID: 16545898 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antioxidants
• Caspase Inhibitors
• Enzyme Inhibitors
• Isoenzymes
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Cytochromes c
• Caspase 2
• Caspases
• Glutathione

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Caspase 2
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Growth Processes (drug effects)
• Cell Survival (drug effects)
• Corbicula (chemistry)
• Cytochromes c (metabolism)
• Drug Interactions
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Glutathione (metabolism)
• HL-60 Cells
• Humans
• Isoenzymes
• Membrane Potentials (drug effects)
• Mitochondrial Membranes (drug effects, physiology)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)