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ID 50726
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Author
Ueno, Tsuyoshi
Toyooka, Shinichi Kakenhi
Ando, Midori
Takaoka, Munenori
Maki, Yuho
Muraoka, Takayuki
Tanaka, Norimitsu
Furukawa, Masashi
Yamatsuji, Tomoki
Naomoto, Yoshio
Abstract
The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24, 100 nM) than the NSCLC cells (p = 0.015). There was significant depletion of both the total and phosphorylated client proteins - EGFR, MET, HERZ and ART - at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G(0)-G(1) cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords
NSCLC
Hsp90
AUY922
EGFR
EGFR-TKI
Mesothelioma
Published Date
2012-04
Publication Title
Lung Cancer
Volume
volume76
Issue
issue1
Publisher
Elsevier Ireland Ltd.
Start Page
26
End Page
31
ISSN
0169-5002
NCID
AA10785743
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1016/j.lungcan.2011.09.011
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/50671
language
英語
Copyright Holders
(C) 2011 Elsevier Ireland Ltd. All rights reserved.
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Refereed
True
DOI
Web of Sience KeyUT