Combination of nitric oxide stimulation with high-dose ¹⁸F-FDG promotes apoptosis and enhances radiation therapy of endothelial cells

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• 作者：Jin-Young Paik ; Jin-Won Park ; Kyung-Ho Jung ; Eun Jeong Lee ; Kyung-Han Lee ; ^{khnm.lee@samsung.com}
• 关键词：FDG ; Endothelial cell ; Radiation therapy ; Tumor ; Angiogenesis ; Apoptosis
• 刊名：Nuclear Medicine and Biology
• 出版年：2012
• 期刊代码：43_09698051
• 类别：ph
• 出版时间：April, 2012
• 卷：39
• 期：3
• 页码：423-428
• 文件大小：298 K

摘要

Introduction

High-dose ¹⁸F-FDG can provide targeted nuclear therapy of cancer. Endothelial cell injury is a key determinant of tumor response to radiotherapy. Here, we tested the hypothesis that activation of endothelial cell glycolytic metabolism with nitric oxide can enhance the therapeutic effect of high-dose ¹⁸F-FDG.

Methods

Calf pulmonary artery endothelial (CPAE) cells were treated with graded doses of ¹⁸F-FDG. Glycolysis was stimulated by 24 h of exposure to the nitric oxide donor, sodium nitroprusside (SNP). Cell viability was assessed by MTT and clonogenic assays. Apoptosis was evaluated by ELISA of cytosolic DNA fragments and Western blots of cleaved caspase-3.

Results

SNP stimulation (0.1 and 1 mM) augmented CPAE cell ¹⁸F-FDG uptake to 2.6- and 4.6-fold of controls without adverse effects. Treatment with 333 渭Ci/ml ¹⁸F-FDG alone reduced viable cell number to 35.4%of controls by Day 3. Combining 0.1 mM SNP stimulation significantly enhanced the killing effect, reducing cell numbers to 19.2%and 39.2%of controls by 333 and 167 渭Ci/ml of ¹⁸F-FDG, respectively. ¹⁸F-FDG also suppressed clonogenic survival to 80.8%and 43.2%of controls by 83 and 167 渭Ci/ml, which was again intensified by SNP to 59.7%and 21.1%of controls. The cytotoxic effect of ¹⁸F-FDG was attributed to induction of apoptosis as shown by increased cytosolic fragmented DNA and cleaved caspase-3 levels (26.4%and 30.7%increases by 167 渭Ci/ml). Combining SNP stimulation significantly increased both of these levels to 1.8-fold of control cells.

Conclusion

High-dose ¹⁸F-FDG combined with nitric oxide-stimulated glycolysis is an effective method to inhibit endothelial cell survival and promote apoptosis. These results suggest a potential role of this strategy for targeted radiotherapy of angiogenic vasculature.