Antiangiogenic properties of 17-(dimethylaminoethylamino)-17- demethoxygeldanamycin: An orally bioavailable heat shock protein 90 modulator

Gurmeet Kaur, Dorina Belotti, Angelika M. Burger, Kirsten Fisher-Nielson, Patrizia Borsotti, Elena Riccardi, Jagada Thillainathan, Melinda Hollingshead, Edward A. Sausville, Raffaella Giavazzi

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Abstract

Purpose: The purpose of this study was to investigate the antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; NSC707545), a water-soluble benzoquinone ansamycin. Experimental Design: The activity of 17-DMAG, in vivo, was evaluated for inhibition of fibroblast growth factor (FGF)-2-induced angiogenesis in s.c. implanted Matrigel in mice. In vitro, the activity of 17-DMAG on endothellal cells (human umbilical vein endothelial cells; HUVEC) was tested in FGF-2; and vascular endothelial growth factor (VEGF)-induced proliferation and apoptosis, motility, and extracellular matrix invasion; and on the alignment of capillary like structures in Matrigel. The protein level of heat shock protein (Hsp)90 and client proteins was examined by Western blot in FGF-2 and VEGF-stimulated HUVEC. Results: Daily oral administration of 17-DMAG affected the angiogenic response in Matrigel in a dose-dependent manner. The hemoglobin content in the Matrigel implants was significantly inhibited, and the histological analysis confirmed a decrease of CD31+ endothelial cells and of structures organized in cord and erythrocyte-containing vessels. In vitro, the compound inhibited dose-dependently the migration and the extracellular matrix-invasiveness of HUVEC and their capacity to form capillary like structures in Matrigel. 17-DMAG treatment also inhibited FGF-2 and VEGF-induced HUVEC proliferation and resulted in apoptosis. Accordingly, the expression of Hsp90 direct client proteins (pAkt and c-Raf-1) or their downstream substrates including pERK was also affected. 17-DMAG consistently increased the expression of Hsp70. Throughout the study similar results were obtained with 17-allylamino-17-demethoxygeldanamycin (17-AAG; NSC3-30507), the analog compound currently undergoing clinical trials. Conclusions: We show that the Hsp90 targeting agents 17-DMAG and 17-AAG inhibit angiogenesis. The strong effects on endothelial cell functions, in vitro, indicate that the antiangiogenic activity of 17-DMAG/17-AAG could also be due to a direct effect on endothelial cells. The oral bioavailability of 17-DMAG might be of advantage in investigating the potential of this compound in clinical trials with antiangiogenic as well as antiproliferative endpoints.

Original languageEnglish
Pages (from-to)4813-4821
Number of pages9
JournalClinical Cancer Research
Volume10
Issue number14
DOIs
Publication statusPublished - Jul 15 2004

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Kaur, G., Belotti, D., Burger, A. M., Fisher-Nielson, K., Borsotti, P., Riccardi, E., Thillainathan, J., Hollingshead, M., Sausville, E. A., & Giavazzi, R. (2004). Antiangiogenic properties of 17-(dimethylaminoethylamino)-17- demethoxygeldanamycin: An orally bioavailable heat shock protein 90 modulator. Clinical Cancer Research, 10(14), 4813-4821. https://doi.org/10.1158/1078-0432.CCR-03-0795