Hiv Protease Inhibitors Enhance the Efficacy of Irradiation.
From: Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Cancer research
- Publish Date: May 2007
- ISSN: 0008-5472
- Volume: 67
- Issue: 10
- Pages: 4886-93
- Medium: Print
- Language: English
- Citation (JAMA): Cuneo Kyle C, Tu Tianxiang, Geng Ling, et al. Hiv Protease Inhibitors Enhance the Efficacy of Irradiation.. Cancer Res. May 2007;67:4886-93
Abstract
Tumor vascular endothelium is rather resistant to the cytotoxic effects of radiation. The HIV protease inhibitors (HPI) amprenavir, nelfinavir, and saquinavir have previously been shown to sensitize tumor cells to the cytotoxic effects of radiation. Additionally, this class of drug has been shown to inhibit angiogenesis and tumor cell migration. Therefore, in the current study, we wanted to determine whether HPIs could enhance the effect of radiation on endothelial function. Our study shows that HPIs, particularly nelfinavir, significantly enhance radiations effect on human umbilical vein endothelial cells (HUVEC) and tumor vascular endothelium. We show that pretreatment of HUVEC with nelfinavir results in enhanced cytotoxicity, including increased apoptosis, when combined with radiation. Moreover, using several functional assays, we show that combination treatment effectively blocks endothelial cell migration and organization. These findings were accompanied by attenuation of Akt phosphorylation, a known pathway for radioresistance. Last, in vivo analysis of tumor microvasculature destruction showed a more than additive effect for nelfinavir and radiation. This study shows that HPIs can enhance the effect of ionizing radiation on vascular endothelium. Therefore, the Food and Drug Administration-approved drug, nelfinavir, may be an effective radiosensitizer in the clinic.
Mesh Headings (Keywords): Apoptosis, Cell Growth Processes, Cell Movement, Cells, Cultured, Endothelial Cells, HIV Protease Inhibitors, Humans, Nelfinavir, Radiation-Sensitizing Agents, Signal Transduction
Check for Full Text / PubMed Unique Identifier (PMID): 17510418
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