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Ann Thorac Surg. 2000 Dec;70(6):1853-60.
Modulation of metastasis phenotypes of non-small cell lung cancer
cells by 17-allylamino 17-demethoxy geldanamycin.
Nguyen DM, Desai S, Chen A, Weiser TS, Schrump DS.
Division of Clinical Sciences, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland 20892, USA.
BACKGROUND:
Cancer cells that overexpress c-erbB oncogenes exhibit resistance to
chemotherapy, enhanced tumorigenicity, as well as increased propensity
for metastasis. The aim of this study was to investigate if depletion of
erbB-1/EGFR and erbB-2/HER2neu oncogene products by 17-allylamino
17-demethoxy Geldanamycin (17AAG) could diminish the metastatic
potential of non-small cell lung cancer (NSCLC) cells that express
varying levels of the erbB1/erbB2 oncogenes.
METHODS:
NSCLC cell lines (H460, H358, H322, or H661) were assayed for
expression of erbB1 and erbB2, the cell adhesion molecule E-cadherin,
secretion of the matrix metalloproteinase 9 (MMP-9), and vascular
endothelial cell growth factor (VEGF), as well as their ability to
invade Matrigel after 48-hour exposure to 17AAG. RESULTS: 17AAG
significantly depleted erbB1 or erbB2 levels in NSCLC cells expressing
high levels of these proteins, and effectively inhibited their growth
with IC50 values ranging from 50 to 90 nmol/L. Moreover, drug treatment
enhanced E-cadherin expression in H322 and H358 cells, and inhibited
secretion of MMP-9 and VEGF secretion by tumor cells. 17AAG diminished
hypoxia-induced upregulation of VEGF expression as well as growth
factor-mediated augmentation of MMP-9 secretion, and profoundly
inhibited the ability of H322 and H358 cells to migrate through Matrigel
in response to chemoattractants.
CONCLUSIONS: In addition to its known
antiproliferative and chemosensitization effects, 17AAGA inhibits the
metastatic phenotype of lung cancer cells. 17AAG may be a novel
pharmacologic agent for specific molecular intervention in lung cancer
patients.
PMID: 11156083
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