Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HPMPC (cidofovir, CDV) is an acyclic nucleoside phosphonate (ANP) with broad-spectrum activity against DNA viruses, including human papillomavirus (HPV). HPMPC has proved to be effective in the treatment of HPV-associated disease in several clinical investigations. In vitro, treatment of HPV-positive cells (compared with normal primary human keratinocytes) with HPMPC has resulted in a concentration- and time-dependent inhibition of cell proliferation. We have now evaluated the mechanism by which this compound induces cell death. Different parameters of apoptosis, that is, (i) induction of CPP32 (caspase-3) protease activity, (ii) translocation of phosphatidylserine (PS) from the inner part of the plasma membrane to the outer layer, (iii) disintegration of the nuclear matrix protein (NMP), (iv) DNA fragmentation, (v) number of cells in apoptotic phase following cell cycle analysis, showed that the mechanism of cell death following treatment with CDV is based on apoptosis. Annexin V staining showed that induction of apoptosis in HPV-positive cells was correlated with a decrease in the percentage of viable cells, while no significant changes in the percentages of living cells were noted in primary human keratinocytes (PHK) cell cultures. Furthermore, a remarkable accumulation of HPMPC-treated cells in the S phase of the cell cycle was observed. Apoptosis induction and S phase arrest were concentration and time dependent. Induction of apoptosis in HPV-positive cells by HPMPC was associated with accumulation of the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitor p21/WAF-1. As HPMPC has proved to induce apoptosis, in a time- and concentration-dependent manner, in a number of HPV-positive cell lines, the regression of papillomatous lesions observed with HPMPC in patients may be due, at least in part, to the induction of apoptosis.
 ...
PMID:Induction of apoptosis by cidofovir in human papillomavirus (HPV)-positive cells. 1169 18

We investigated the signal-transduction pathway of canine distemper virus-Onderstepoort (CDV-Ond) vaccine strain-mediated apoptosis in Vero cells. Canine distemper virus-Onderstepoort at a multiplicity of infection (MOI) of 0.1 induced DNA fragmentation 48 h after infection. Immunofluorescence staining revealed that 57% +/- 4% of the CDV-N-protein-positive cells were terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive, and all TUNEL-positive cells were CDV-N-protein-positive, indicating that CDV-Ond induced apoptosis only in the infected cells. We also found that CDV-Ond infection induced activation of caspase-3 and caspase-8. In the semi-quantitative reverse transcription-polymerase chain reaction assay for apoptosis-related genes, the expression of mRNA of the death receptor, Fas, was also increased in CDV-Ond-infected cells. In contrast, the expressions of Bcl-2 and Bax, regulators for intrinsic apoptotic signaling through the mitochondria, did not change. These results suggest that CDV-Ond induced apoptosis by activating caspase-3, possibly through caspase-8 signaling rather than through p53/Bax-mediated, mitochondrial signaling in the infected cells.
 ...
PMID:Canine distemper virus induces apoptosis through caspase-3 and -8 activation in vero cells. 1690 58

Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; (S)-HPMPC] is an antiviral drug that has been approved for the treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir also possesses potent activity against human papillomavirus-induced tumors in animal models and patients. We have recently shown that cidofovir inhibits the development of vascular tumors induced by basic fibroblast growth factor (FGF2)-overexpressing endothelial cells (FGF2-T-MAE) in mice. Here, we demonstrate that the inhibitory activity of cidofovir in FGF2-T-MAE cells may result from the specific induction of apoptosis. Cell cycle analysis revealed that cidofovir induces accumulation of cells in the S phase and, upon prolonged treatment, a significant increase in sub-G1 cells, exhibiting a subdiploid DNA content. Moreover, annexin V binding, an early event in apoptosis induction, was increased in cidofovir-treated FGF2-T-MAE cells. Cidofovir also caused nuclear fragmentation and the activation of caspase-3-like proteases, as evidenced by the cleavage of poly(ADP-ribose)polymerase. In addition, cidofovir treatment of FGF2-T-MAE cells resulted in a pronounced up-regulation of the tumor suppressor protein p53. However, the expression of Bax and Bcl-2 remained unchanged, and cidofovir did not induce the release of cytochrome c from the mitochondria. In addition, cidofovir did not suppress the phosphorylation of protein kinase B/Akt, a transmitter of antiapoptotic survival signals, or its downstream regulator Bad, indicating that the Akt pathway is not affected by cidofovir in FGF2-T-MAE cells. However, the compound inhibited the expression of FGF2 and FGF2 signaling through Erk42/44, as shown by Western blot analysis. Our results indicate that cidofovir inhibits the growth of FGF2-T-MAE cells via inhibition of FGF2 expression and signaling and via the induction of apoptosis. These findings suggest that the clinical use of cidofovir might be expanded to tumors that are not induced by oncogenic viruses.
 ...
PMID:The nucleotide analog cidofovir suppresses basic fibroblast growth factor (FGF2) expression and signaling and induces apoptosis in FGF2-overexpressing endothelial cells. 1715