Activation of p53 protein in normal and in tumor cells by a novel anticancer agent CHS 828.
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.
Wojciechowski
J
J
Institute of Cancer Research, University of Vienna, Vienna, Austria. Jozefa.Antonia.Gadek-Wesierski@univie.ac.at
Lövborg
H
H
Wesierska-Gadek
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003486:Cyanides / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D010766:Phosphorylation; D011064:Poly Adenosine Diphosphate Ribose / Q000172:deficiency / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D000970:Antineoplastic Agents; D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D016159:Tumor Suppressor Protein p53; D011064:Poly Adenosine Diphosphate Ribose; D004247:DNA