Radiosensitization of Human Vascular Endothelial Cells Through Hsp90 Inhibition With 17-N-Allilamino-17-Demethoxygeldanamycin

Journal Article · Tue Jul 01 04:00:00 EDT 2008 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2008.02.034· OSTI ID:21124326

Makarova, Yulia M; Malyutina, Yana V ^[1]

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1. Department of Radiation Biochemistry, Medical Radiology Research Center, Obninsk (Russian Federation)

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.

• OSTI ID: 21124326
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 3 Vol. 71; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ANTINEOPLASTIC DRUGS
APOPTOSIS
BIOTIN
DEOXYURIDINE
FIBROBLASTS
GAMMA RADIATION
GROWTH FACTORS
HEAT-SHOCK PROTEINS
INHIBITION
IRRADIATION
MORPHOGENESIS
NEOPLASMS
PHOSPHORYLATION
RADIOSENSITIVITY
RADIOTHERAPY
TUMOR CELLS
VEINS