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)

We investigated the mechanisms of inhibitory effect of growth hormone-releasing hormone (GHRH) antagonist JMR-132 on the growth of HT29, HCT-116 and HCT-15 human colon cancer cells in vitro and in vivo. High-affinity binding sites for GHRH and mRNA for GHRH and splice variant-1 (SV1) of the GHRH receptor were found in all three cell lines tested. Proliferation of HT-29, HCT-116 and HCT-15 cells was significantly inhibited in vitro by JMR-132. Time course studies revealed that the treatment of human HCT-116 colon cancer cells with 10 muM GHRH antagonist JMR-132 causes a significant DNA damage as shown by an increase in olive tail moment (OTM) and loss of inner mitochondrial membrane potential (Delta Psi m). Western blotting demonstrated a time-dependent increase in protein levels of phospho-p53 (Ser46), Bax, cleaved caspase-9, -3, cleavage of poly(ADP-ribose)polymerase (PARP) and a decrease in Bcl-2 levels. An augmentation in cell cycle checkpoint protein p21(Waf1/Cip1) was accompanied by a cell cycle arrest in S-phase. DNA fragmentation visualized by the comet assay and the number of apoptotic cells increased time dependently as determined by flow cytometric annexinV and PI staining assays. In vivo, JMR-132 decreased the volume of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic mice up to 75% (p < 0.05) and extended tumor doubling time (p < 0.001). Our observations suggest that GHRH antagonist JMR-132 exerts its antiproliferative effect on experimental colon cancer cells through p21(Waf1/Cip1) mediated S-phase arrest along with apoptosis involving the intrinsic pathway.
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PMID:GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells. 1975 49

Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) with limited treatment options. It is known that liver regeneration following APAP-induced ALF is a deciding factor in the final outcome. Previous studies from our laboratory using an incremental dose model involving a regenerating (300 mg/kg, APAP300) and a nonregenerating (600 mg/kg, APAP600) dose of APAP in mice have revealed several proregenerative pathways that regulate regeneration after APAP overdose. Here we report that DNA damage and repair mechanisms regulate initiation of liver regeneration following APAP overdose. Mice treated with nonregenerating APAP600 dose showed prolonged expression of pH2AX, a marker of the DNA double-strand break (DSB), compared with APAP300. In regenerating APAP300 dose-treated mice, H2AX was rapidly dephosphorylated at Tyr142, indicating timely DNA repair. Expression of several DNA repair proteins was substantially lower with APAP600. Poly(ADP) ribose polymerase (PARP) activation, involved in DNA repair, was significantly higher in the APAP300 group compared to the APAP600 group. Activation of p53, the major cell cycle checkpoint protein, was significantly higher with APAP600 as demonstrated by substantially higher expression of its target genes. Taken together, these data show that massive DNA DSB occurs in high-dose APAP toxicity, and lack of prompt DSB repair after APAP overdose leads to prolonged growth arrest and proliferative senescence, resulting in inhibited liver regeneration.
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PMID:DNA Damage Response Regulates Initiation of Liver Regeneration Following Acetaminophen Overdose. 2954 Feb 58