Artikel
Influence of p21 and p53 on HDAC-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo
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Veröffentlicht: | 20. März 2006 |
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Gliederung
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Background: Inhibitors of histone deacetylases (HDAC-I) have been shown to exert anti-tumoral effects on different human cancers both in vitro and in vivo. We therefore investigated the effect of a novel HDAC-I, A-422378.0, on wild-type HCT116 colon cancer cells as well as derivatives lacking either p21 or p53.
Methods: Cell lines were incubated with A-422378.0 at different concentrations (0.001 to 10 µM) for 3 to 120 h. Cell viability, proliferation and apoptosis rates were determined quantitatively and verified qualitatively by western blotting, detection of mitochondrial membrane potential breakdown, activation of caspases 3 and 8 and cytokeratin 18 cleavage.A subcutaneous xenograft model was established in NMRI mice. Animals were treated with daily intraperitoneal injections of 10 mg/kg for 14 days. Tumor size was measured, proliferation and apoptosis rate were determined immunohistochemically.
Results: All three HCT116 cell lines responded to A-422378.0 treatment with a time- and dose-dependent induction of apoptosis with p21-/- cells being more sensitive than wild-type or p53-/- cells. Apoptosis induction was induced by breakdown of DYm. Caspase 3 was activated in wild-type cells only. Xenografts showed a pronounced growth inhibition upon HDAC-I treatment, paralleled by down-regulation of PCNA and induction of apoptosis.
Conclusions: Treatment of wild-type or knock-out HCT116 cells with A-422378.0 exerts potent anti-proliferative and pro-apoptotic effects in vitro and in vivo. Loss of p53 leads to resistance to this treatment, while HCT116 cells deficient in p21 are sensitised to HDAC-inhibitor mediated apoptosis. A-422378.0 might therefore be a potent new therapeutic compound for the treatment of advanced colorectal cancers.