Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and the ADP-ribosylation inhibitor 3-aminobenzamide (3-ABA) in the cytotoxicity induced by the novel antitumoral cyanoguanidine CHS 828 was investigated in the human lymphoma cell line U-937 GTB. Exposing cells to CHS 828 and 3-ABA in combination resulted in a 100-fold higher IC(50) compared to exposure to CHS 828 alone. CHS 828 did not activate PARP, measured as PARP-activity and formation of poly(ADP-ribose). The ATP-levels and levels of extracellular acidification rate of cells exposed to CHS 828 in combination with 3-ABA were maintained for a longer period than for cells exposed to CHS 828 alone. To characterize the mode of cell death, caspase-3 activity and gross morphology were assessed. 3-ABA increased and delayed the caspase-3 activity in cells exposed to CHS 828. Cells exposed to high concentrations of CHS 828 showed a necrotic morphology, while high concentrations of CHS 828 in combination with 3-ABA switched the mode of cell death, generating an apoptotic morphology. The results indicate that the cytotoxicity and morphology induced by CHS 828 is not due to PARP activation but can be modulated by the ADP-ribosylation inhibitor 3-ABA.
 ...
PMID:Modulation of pyridyl cyanoguanidine (CHS 828) induced cytotoxicity by 3-aminobenzamide in U-937 GTB cells. 1199 91

We observed stronger cytotoxic effect of CHS 828 on poly(ADP-ribose) polymerase-1(PARP-1) knock-out cells as compared with the normal counterpart. The proliferation of PARP-1 -/- cells was inhibited by a drug concentration approximately 3-fold lower than that in the normal cells. The monitoring of p53 levels revealed that CHS 828 induced p53 response in a dose-dependent manner in only normal cells. The drug, however, failed to activate the p53 protein in PARP-1-deficient cells even after combined treatment with multidrug-resistant modulators. These results show that the PARP-1 inactivation sensitizes cells to the novel anticancer drug CHS 828 and that the drug is able to activate different cellular pathways depending on PARP-1 status.
 ...
PMID:Action of a novel anticancer agent, CHS 828, on mouse fibroblasts: increased sensitivity of cells lacking poly (ADP-Ribose) polymerase-1. 1215 20

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.
 ...
PMID:Activation of p53 protein in normal and in tumor cells by a novel anticancer agent CHS 828. 1295 35