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

Ann Thorac Surg. 2000 Dec;70(6):1853-60. doi: 10.1016/s0003-4975(00)01810-5.


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.

MeSH terms

  • Benzoquinones
  • Cadherins / metabolism
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Dose-Response Relationship, Drug
  • Endothelial Growth Factors / antagonists & inhibitors
  • Endothelial Growth Factors / genetics
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lactams, Macrocyclic
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / genetics
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase Inhibitors
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / genetics
  • Rifabutin / analogs & derivatives
  • Rifabutin / pharmacology*
  • Tumor Cells, Cultured / drug effects*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Benzoquinones
  • Cadherins
  • Endothelial Growth Factors
  • Lactams, Macrocyclic
  • Lymphokines
  • Matrix Metalloproteinase Inhibitors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Rifabutin
  • tanespimycin
  • ErbB Receptors
  • Receptor, ErbB-2
  • Matrix Metalloproteinase 9