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)

Nucleolin is specifically transported to the surface of proliferating endothelial cells in vitro and in vivo. In contrast to its well defined functions in the nucleus and cytoplasm, the function of cell surface nucleolin is poorly defined. We have previously identified the nucleolin-binding antibody NCL3 that specifically binds to cell surface nucleolin on angiogenic blood vessels in vivo and is internalized into the cell. Here, we show that NCL3 inhibits endothelial tube formation in vitro as well as angiogenesis in the matrigel plaque assay and subcutaneous tumor models in vivo. Intriguingly, the specific targeting of proliferating endothelial cells by NCL3 in subcutaneous tumor models leads to the normalization of the tumor vasculature and as a result to an increase in tumor oxygenation. Treatment of endothelial cells with anti-nucleolin antibody NCL3 leads to a decrease of mRNA levels of the anti-apoptotic molecule Bcl-2 and as a consequence induces endothelial cell apoptosis as evidenced by PARP cleavage. These data reveal a novel mode of action for anti-angiogenic therapy and identify cell surface nucleolin as a novel target for combinatorial chemotherapy.
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PMID:Cell surface nucleolin antagonist causes endothelial cell apoptosis and normalization of tumor vasculature. 1922 98

DNA double-strand breaks (DSBs) induced during clinical radiotherapy are potent inducers of cell death. Poly(ADP-ribose) polymerase (PARP)-1 is a 113-kD nuclear protein that binds to both single- and double-strand DNA breaks and is actively involved in DNA single-strand break repair and base excision repair. Recently, potent and specific chemical inhibitors of PARP activity have been developed that are effective tumor cell radiosensitizers in vitro and in vivo. Because of synthetic lethality, PARP inhibitors may be highly effective as a single agent in patients whose tumors have germline or somatic defects in DNA damage and repair genes (eg, ATM, BRCA1, BRCA2, and NBS1) or defects in genes involved in phosphatase and tensin homolog gene (PTEN) signaling. Defects in specific DNA repair pathways also appear to enhance the radiosensitizing effects of PARP inhibition. In addition to inherent genetics, tumor cells may also be preferentially sensitized to radiotherapy by diverse mechanisms, including proliferation-dependent radiosensitization, targeting of the endothelium and tumor vasculature, and increased sensitivity to PARP inhibitors within repair-deficient hypoxic cells. Because biologically active doses of PARP inhibitors caused minimal toxicity in phase I to II clinical trials, careful scheduling of these agents in combination with radiotherapy may maintain the therapeutic ratio and increase tumor radiocurability.
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PMID:Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. 2083 20

The present study embodies a detailed investigation of the chemoenhancement property of a synthetic organoselenium compound, 2-[5-selenocyanato-pentyl]-7-amino benzo[de]isoquinoline-1,3-dione (ANOS) in tumor bearing Swiss albino mice. The results accumulated from this study illustrated that the administration of ANOS significantly potentiated the therapeutic efficacy of cyclophosphamide by reducing the tumor burden and chemotherapy induced toxicity in the host. Ability of ANOS in inducing apoptosis and inhibiting angiogenesis was thought to be the crucial effecter for enhancing the therapeutic efficacy of cyclophosphamide. Fluorescence microscopic study revealed that ANOS was capable of penetrating tumor cells and distributed in the subcellular compartments. We showed that ANOS-induced apoptosis, as evidenced by the TUNEL assay and cleavage of poly(ADP-ribose) polymerase (PARP), involved ROS production and DNA damage in tumor cells. ROS production subsequently activated p53 phosphorylation at Ser-15. This in turn activated cytochrome c (cyt c) release from mitochondria via Bcl-2 and Bax. Finally activation of caspase 3 led to PARP cleavage and apoptosis. These results suggested that p53 dependent mitochondrial pathway was playing an important role in ANOS induced apoptosis of tumor cells. Administration of ANOS also resulted in significant improvement of tumor vasculature and sprouting of the peritoneal cavity along with the normalization of MMP-9 level in serum and ascites fluid of tumor bearing mice. This potential antiangiogenic activity of ANOS also facilitated the therapeutic efficacy of the combination therapy. Furthermore, ANOS significantly suppressed cyclophosphamide-induced liver, hematopoietic and genetic damages. A concomitant decrease in drug-induced toxicity by ANOS might also have enhanced the efficacy of cyclophosphamide by improving the intrinsic defense machineries of the host.
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PMID:2-[5-Selenocyanato-pentyl]-6-amino-benzo[de]isoquinoline-1,3-dione inhibits angiogenesis, induces p53 dependent mitochondrial apoptosis and enhances therapeutic efficacy of cyclophosphamide. 2503 69