D M Nguyen1, S Desai, A Chen, T S Weiser, D S Schrump. 1. Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. dao_nguyen@nih.gov
Abstract
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 (17AAGA) 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 17AAGA. RESULTS: 17AAGA 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. 17AAGA 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. 17AAGA may be a novel pharmacologic agent for specific molecular intervention in lung cancer patients.
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 (17AAGA) 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 17AAGA. RESULTS: 17AAGA 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. 17AAGA 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. 17AAGA may be a novel pharmacologic agent for specific molecular intervention in lung cancerpatients.
Authors: Claire Marie-Elisabeth Sauvageot; Jessica Leigh Weatherbee; Santosh Kesari; Susan Elizabeth Winters; Jessica Barnes; Jamie Dellagatta; Naren Raj Ramakrishna; Charles Dean Stiles; Andrew Li-Jen Kung; Mark W Kieran; Patrick Yung Chih Wen Journal: Neuro Oncol Date: 2008-08-05 Impact factor: 12.300