Modulation of metastasis phenotypes of non-small cell lung cancer cells by 17-allylamino 17-demethoxy geldanamycin.
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.
Nguyen
D M
DM
Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. dao_nguyen@nih.gov
Desai
S
S
Chen
A
A
Weiser
T S
TS
Schrump
D S
DS
D016227:Benzoquinones; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D017828:Rifabutin / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016227:Benzoquinones; D015820:Cadherins; D016228:Endothelial Growth Factors; D066246:ErbB Receptors; D047029:Lactams, Macrocyclic; D008222:Lymphokines; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D017828:Rifabutin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C112765:tanespimycin