cytochrome-c-t and damnacanthal

The effect of the natural compound damnacanthal from Morinda citrifolia on SKHep 1 cell growth regulation was investigated. Treatment of SKHep 1 cells with damnacanthal for 24h indicated a dose-dependent antiproliferative activity. Damnacanthal seems to be selective for tumor cell lines, since there is only minimal toxicity against normal hepatocyte cells (FL83B). This is first demonstration that damnacanthal-mediated apoptosis involves the sustained activation of the p38 MAPK pathway, leading to the transcription of the death receptor family genes encoding DR5/TRAIL and TNF-R1/TNF-α genes as well as the p53-regulated Bax gene. The damnacanthal-mediated expression of DR5/TRAIL and TNF-R1/TNF-α results in caspase 8 activation, leading to Bid cleavage. In turn, activated Bid, acting with p53-regulated Bax, leads to cytochrome c released from mitochondria into the cytoplasm. Combined activation of the death receptors and mitochondrial pathways results in activation of the downstream effecter caspase 3, leading to cleavage of PARP. TRAIL- and TNF-α-mediated damnacanthal-induced apoptosis could be suppressed by treatment with caspase inhibitors as well as soluble death receptors Fc:DR5 and Fc:TNF-R1 chimera. Taken together, this study provided first evidence demonstrating that TRAIL-, TNF-α-, and p53-mediated damnacanthal-induced apoptosis require the activation of p38 MAPK and mitochondrion-mediated caspase-dependent pathways.

Topics: Animals; Anthraquinones; Apoptosis; bcl-2-Associated X Protein; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cytochromes c; Cytosol; Enzyme Activation; Humans; Membrane Potentials; Mitochondria; p38 Mitogen-Activated Protein Kinases; Poly(ADP-ribose) Polymerases; Protein Transport; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53