Modulation of metastasis phenotypes of non-small cell lung cancer cells by17-allylamino 17-demethoxy geldanamycin

Background. Cancer cells that overexpress c-erbB oncogenes exhibit resistan ce to chemotherapy, enhanced tumorigenicity, as well as increased propensit y 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-demeth oxy Geldanamycin (17AAGA) could diminish the metastatic potential of non-sm all 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 expr ession of erbB1 and erbB2, the cell adhesion molecule E-cadherin, secretion of the matrix metalloproteinase 9 (MMP-9), and vascular endothelial cell g rowth factor (VEGF), as well as their ability to invade Matrigel after 48-h our 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 IC,, values ranging from 50 to 90 nmol/L. Moreover, drug treatm ent enhanced E-cadherin expression in H322 and H358 cells, and inhibited se cretion of MMP-9 and VEGF secretion by tumor cells. 17AAGA diminished hypox ia-induced upregulation of VEGF expression as well as growth factor-mediate d augmentation of MMP-9 secretion, and profoundly inhibited the ability of H322 and H358 cells to migrate through Matrigel in response to chemoattract ants. Conclusions. In addition to its known antiproliferative and chemosensitizat ion effects, 17AAGA inhibits the metastatic phenotype of lung cancer cells. 17AAGA may be a novel pharmacologic agent for specific molecular intervent ion in lung cancer patients. (Ann Thorac Surg 2000;70:1853-60) ( C) 2000 by The Society of Thoracic Surgeons.