Effects of the tyrosine-kinase inhibitor geldanamycin on ligand-induced Her-2/neu activation, receptor expression and proliferation of Her-2-positive malignant cell lines

Int J Cancer. 1997 Jan 17;70(2):221-9. doi: 10.1002/(sici)1097-0215(19970117)70:2<221::aid-ijc14>3.0.co;2-l.


Geldanamycin belongs to the family of benzoquinoid ansamycin tyrosine-kinase inhibitors. We have examined its effects on Her-2/neu kinase activity, protein expression level, and proliferation of Her-2+ malignant cells. In SK-BR-3 breast-cancer cells, short-time treatment with geldanamycin completely abrogated gp30-ligand-induced activation of Her-2 without a change of receptor-expression level. Longer treatment of intact cells with geldanamycin induced decreased steady-state Her-2 autophosphorylation activity, which correlated with reduction of Her-2 protein expression and phosphotyrosine content of several proteins. The decrease was time- and dose-dependent, starting after 1 hr at 100 nM concentration and reaching completion by 24 hr. The reduction of the Her-2 protein level probably resulted from increased degradation, since the Her-2 mRNA level remained constant. Geldanamycin effects were not specific for Her-2, since the non-receptor tyrosine-kinase fyn was inhibited equally. In contrast to these results, protein-kinase-C activity was not affected. In 3 other malignant cell lines expressing different amounts of Her-2 (SK-BR-3 > SK-OV-3 > OVCAR3 > MCF7), geldanamycin also effectively reduced Her-2-kinase activity proportionally to the decrease of protein expression. In contrast, in a [3H]-thymidine-uptake assay, cell growth was meaningfully inhibited by geldanamycin at nanomolar concentrations only in SK-BR-3 (IC50 2 nM) and MCF7 (IC50 20 nM), while OVCAR3 was only moderately sensitive (IC50 2 microM) and SK-OV-3 was clearly resistant to geldanamycin. In direct comparison with herbimycin A, another benzoquinoid ansamycin that has been more thoroughly characterized, the biologic effects of geldanamycin were more pronounced.

Publication types

  • Comparative Study

MeSH terms

  • Adenocarcinoma / pathology
  • Benzoquinones
  • Breast Neoplasms / pathology
  • Cell Division / drug effects
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lactams, Macrocyclic
  • Ligands
  • Neoplasm Proteins / antagonists & inhibitors*
  • Ovarian Neoplasms / pathology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Quinones / pharmacology*
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Rifabutin / analogs & derivatives
  • Tumor Cells, Cultured


  • Benzoquinones
  • Enzyme Inhibitors
  • Lactams, Macrocyclic
  • Ligands
  • Neoplasm Proteins
  • Quinones
  • RNA, Messenger
  • RNA, Neoplasm
  • Rifabutin
  • herbimycin
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • geldanamycin