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Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):858-65. doi: 10.1016/j.ijrobp.2008.02.034. Epub 2008 Apr 12.

Radiosensitization of human vascular endothelial cells through Hsp90 inhibition with 17-N-allilamino-17-demethoxygeldanamycin.

Author information

1
Department of Radiation Biochemistry, Medical Radiology Research Center, Obninsk, Russia. aekabakov@hotmail.com

Abstract

PURPOSE:

In addition to invasive tumor cells, endothelial cells (ECs) of the tumor vasculature are an important target for anticancer radiotherapy. The purpose of the present work is to investigate how 17-N-allilamino-17-demethoxygeldanamycin (17AAG), known as an anticancer drug inhibiting heat shock protein 90 (Hsp90), modifies radiation responses of human vascular ECs.

METHODS AND MATERIALS:

The ECs cultured from human umbilical veins were exposed to gamma-irradiation, whereas some EC samples were pretreated with growth factors and/or 17AAG. Postirradiation cell death/survival and morphogenesis were assessed by means of terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick end labeling or annexin V staining and clonogenic and tube-formation assays. The 17AAG-affected expression and phosphorylation of radioresistance-related proteins were probed by means of immunoblotting. Dominant negative or constitutively activated Akt was transiently expressed in ECs to manipulate Akt activity.

RESULTS:

It was found that nanomolar concentrations of 17AAG sensitize ECs to relatively low doses (2-6 Gy) of gamma-irradiation and abolish the radioprotective effects of vascular endothelial growth factor and basic fibroblast growth factor. The drug-induced radiosensitization of ECs seems to be caused by prevention of Hsp90-dependent phosphorylation (activation) of Akt that results in blocking the radioprotective phosphatidylinositol 3-kinase/Akt pathway.

CONCLUSIONS:

Clinically achievable concentrations of 17AAG can decrease the radioresistance intrinsic to vascular ECs and minimize the radioprotection conferred upon them by tumor-derived growth factors. These findings characterize 17AAG as a promising radiosensitizer for the tumor vasculature.

PMID:
18410996
DOI:
10.1016/j.ijrobp.2008.02.034
[Indexed for MEDLINE]

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