CHS 828, a novel
cyanoguanidine, represents a new class of drugs for
cancer therapy, with an unknown primary mechanism of action. It is generally known that anticancer drugs induce p53 response thereby triggering cell cycle arrest or apoptosis. We investigated the effect of
CHS 828 on p53 response in normal and
tumor cells and compared this effect with that exerted by conventional anticancer drugs. After 24 h of treatment with
CHS 828, we observed a dose-dependent up-regulation of wild type (WT) p53
protein in human
breast carcinoma MCF-7 cells as well as in normal human and mouse fibroblasts. The highest p53 increase was observed at 300 nM to 1 microM
CHS 828.
CHS 828 induced phosphorylation of p53
protein at Ser-15 in normal cells. However, the
drug failed to induce p53
protein in mouse cells in which the poly(ADP-ribose)-1 gene (PARP-1) was disrupted even at a 30-fold higher dose and after prolonged treatment. Combined treatment of PARP-1 -/- cells by multidrug resistance modulators did not alter p53 expression.
CHS 828 inhibited cell proliferation and DNA replication in the tested cells. Interestingly,
DNA synthesis as well as proliferation of PARP-1 deficient cells was inhibited by
drug concentrations that were approximately 3-fold lower than their conventional counterparts. Treatment of cells with
CHS 828 for 48 h did not induce apoptosis.