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 heat shock protein (HSP) 90 chaperone machine involved in numerous oncogenic signaling pathways is overexpressed in cancer cells and is currently being evaluated for anticancer therapy. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a heterogeneous group of tumors with increasing incidence and poor prognosis. Here, we report the antiproliferative effects of the HSP90 inhibitors AUY922 and HSP990 in neuroendocrine tumor cells. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727 and midgut carcinoid GOT1 neuroendocrine tumor cells with increasing concentrations of AUY922 and HSP990 dose-dependently suppressed cell viability. Significant effects on neuroendocrine cell viability were observed with inhibitor concentrations as low as 5 nM. Inhibition of cell viability was associated with the induction of apoptosis as demonstrated by an increase in sub-G1 events and PARP cleavage. HSP90 inhibition was associated with decreased neuroendocrine ErbB and IGF-I receptor expression, decreased Erk and Akt phospho-rylation and the induction of HSP70 expression. These findings provide evidence that targeted inhibition of upregulated HSP90 activity could be useful for the treatment of aggressive neuroendocrine tumors resistant to conventional therapy.
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PMID:Potent antitumor activity of the novel HSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells. 2410 Apr 69

Metformin is a widely used oral antidiabetic drug with good tolerability. Recent studies suggest that it also possesses adjuvant potent anticancer properties in a variety of tumors. Neuroendocrine tumors (NETs) of the gastro-entero-pancreatic system (GEP) comprise a heterogeneous group of tumors with increasing incidence and limited effective therapeutic options. Here we report the antiproliferative effects of metformin in neuroendocrine tumor cells in vitro. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727, and midgut GOT1 neuroendocrine tumor cells with increasing concentrations of metformin (0.1-10 mM) dose-dependently suppressed cell viability and cell counts. Metformin induced AMPK phosphorylation in pancreatic BON1 and midgut GOT1 but suppressed AMPK activity in bronchopulmonary NCI-H727. Thus, AMPK-dependent and AMPK-independent properties may be operative in NETs of different origin. Metformin suppressed mTORC1 signaling in all three tumor cell types, evidenced by suppression of 4EBP1, pP70S6K, and S6 phosphorylation, and was associated with compensatory AKT activity. We observed induction of ERK phosphorylation in BON1 and NCI-H727 and inhibition of ERK in midgut GOT1 cells, while all three tumor cell types responded with induction of GSK3 phosphorylation. This suggests a central role for GSK3 in metformin-mediated signal transduction. Inhibition of cell proliferation by metformin was associated with apoptosis induction only in midgut GOT1, evidenced by increased subG0/1 fraction and PARP cleavage. These results suggest a potential role of metformin as a (adjuvant) therapeutic for patients with NETs.
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PMID:Anticancer effects of metformin on neuroendocrine tumor cells in vitro. 2540 73