Potent antitumor activity of the novel HSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells

Autor: Kathrin Zitzmann, Felix Beuschlein, George Vlotides, Julian Maurer, Gerald Spoettl, Galina Ailer, Burkhard Göke, Christoph J. Auernhammer
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Cancer Research
Lung Neoplasms
Cell Survival
Pyridones
Receptor
ErbB-2
Receptor expression
Apoptosis
Cell Cycle Proteins
Carcinoid Tumor
Neuroendocrine tumors
Biology
Receptor
IGF Type 1
ErbB
Cell Line
Tumor
medicine
Humans
HSP70 Heat-Shock Proteins
Viability assay
HSP90 Heat-Shock Proteins
heat shock protein 90
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Protein kinase B
Neuroendocrine cell
Adaptor Proteins
Signal Transducing
Cell Proliferation
Ribosomal Protein S6 Kinases
70-kDa
Articles
Isoxazoles
Resorcinols
Cell cycle
medicine.disease
Phosphoproteins
Carcinoma
Neuroendocrine
Pancreatic Neoplasms
medicine.anatomical_structure
Pyrimidines
Oncology
Cancer cell
gastroenteropancreatic
Cancer research
M Phase Cell Cycle Checkpoints
heat shock protein 90 inhibitors
Poly(ADP-ribose) Polymerases
Proto-Oncogene Proteins c-akt
neuroendocrine tumor
Signal Transduction
Zdroj: International Journal of Oncology
ISSN: 1791-2423
1019-6439
Popis: 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.
Databáze: OpenAIRE
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