Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic carcinoma is relatively resistant to chemotherapy and cell death induced by replication of adenoviruses (Ad) can be one of the therapeutic options. Transduction efficacy of conventional type 5 Ad (Ad5) is however low and the cytotoxic mechanism by replication-competent Ad was not well understood. We constructed replication-competent Ad5 of which the E1A promoter region was replaced with a transcriptional regulatory region of the midkine, the survivin or the cyclooxygenase-2 gene, all of which were expressed at a high level in human tumors. We also prepared replication-competent Ad5 that were activated with the same region but had the type 35 Ad-derived fiber-knob region (AdF35) to convert the major cellular receptor for Ad infection from the coxsackie adenovirus receptor to CD46 molecules. Replication-competent AdF35 that were activated with the exogenous region produced cytotoxic effects on human pancreatic carcinoma cells greater than the corresponding Ad5 bearing with the same regulatory region. Cells infected with the AdF35 showed cytopathic effects and increased sub-G1 fractions. Caspase-9, less significantly caspase-8 and poly (ADP-ribose) polymerase, but not caspase-3 was cleaved and expression of molecules involved in autophagy and caspase-independent cell death pathways remained unchanged. Nevertheless, H2A histone family member X molecules were phosphorylated, and N-acetyl-L-cystein, an inhibitor for reactive oxygen species, suppressed the AdF35-mediated cytotoxicity. These data indicated a novel mechanism of Ad-mediated cell death and suggest a possible clinical application of the fiber-knob modified Ad.
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PMID:Replication-competent adenoviruses with the type 35-derived fiber-knob region achieve reactive oxygen species-dependent cytotoxicity and produce greater toxicity than those with the type 5-derived region in pancreatic carcinoma. 2637 51

Pseudolaric acid B (PAB) is a diterpene-type acid isolated from the root and trunk bark of Pseudolarix kaempferi Gordon of the Pinaceae family that has been demonstrated to induce apoptosis in various cell lines and autophagy in certain cell lines including murine fibrosarcoma L929, human thyroid squamous cell carcinoma SW579 and human lung fibroblast MRC5 cells. However, in human rhabdomyosarcoma RD cells, which are derived from the most common soft tissue sarcoma in children and represent a high-grade neoplasm of a skeletal myoblast type, it is not clear whether PAB induces apoptosis or autophagy. The identification of the exact mechanism of PAB is important for studying its antitumor effects and its potential application in the treatment of human rhabdomyosarcoma. To confirm the inhibitory ability of PAB on RD cells, the inhibitory ratio of PAB was analyzed, and the results of MTT assay demonstrated that PAB inhibited RD cell proliferation. Meanwhile aggregation of the microtubule fibers was found in PAB-treated RD cells compared with that in control-treated cells, which was consistent with previous studies. In addition, PAB inhibited RD cell migration, induced apoptosis and cell cycle arrest at the G2/M phase. These results suggested that the mechanism of PAB-mediated growth inhibition in RD was similar to that reported in the human breast cancer cell line MCF-7 and the neuroglioma cell line A172; however, it was different from that reported in the L929, MRC5 and SW579 cell lines. Additional experiments demonstrated that PAB regulated the activation of caspase-8 and caspase-9 to induce apoptosis and caused an upregulation of phosphorylated H2A histone family member X and cyclin B1 expression in order to induce cell cycle arrest. Therefore, PAB may be considered a potential treatment agent for human rhabdomyosarcoma.
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PMID:Pseudolaric acid B induces apoptosis in human rhabdomyosarcoma RD cells. 3313 58