Ciprofloxacin as a potential radio-sensitizer to tumor cells and a radio-protectant for normal cells: differential effects on γ-H2AX formation, p53 phosphorylation, Bcl-2 production, and cell death.
Ciprofloxacin as a potential radio-sensitizer to tumor cells and a radio-protectant for normal cells: differential effects on γ-H2AX formation, p53 phosphorylation, Bcl-2 production, and cell death.
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DOI：
10.1007/s11010-014-2053-z
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发表时间：
2014-08
影响因子：
4.3
通讯作者：
Fukumoto R
中科院分区：
文献类型：
--
作者：
Kiang JG;Garrison BR;Smith JT;Fukumoto R
电离辐射以剂量依赖的方式增加细胞死亡率。DNA双链断裂、γ-H_2AX、P53磷酸化以及P53和BAX蛋白水平的增加也会发生。我们研究了被广泛使用的抗生素环丙沙星(CIP)抑制电离辐射引起的DNA损伤的能力。用2~8Gy60Co-−/−光子照射人肿瘤TK6、NH32(TK6的P53-γ)细胞和正常人外周血单个核细胞。检测γ-H_2AX(DNA链断裂指标)、磷酸化P53(导致细胞周期停滞)、Bcl2、凋亡蛋白和细胞死亡。电离辐射在1小时内以剂量依赖的方式增加γ-H_2AX在TK6细胞(p53+/+)中的含量。环磷酰胺治疗前后均能有效抑制γ-H_2AX的升高。CIP处理可减少Bcl2的产生，但促进P53的磷酸化、caspase-3的活化和细胞死亡。在NH_(32)细胞中，CIP不能显著抑制辐射诱导的γ-H_2AX升高，提示CIP抑制作用参与了P53依赖的机制。在正常人外周血单核细胞中，CIP不能阻断辐射诱导的γ-H_2AX的增加，但能有效地增加Bc l-2的产生，但能阻止P53的磷酸化增加和随后的细胞死亡。CIP照射后24小时GADD45α表达增加，p21蛋白表达增强。结果提示，CIP在TK6细胞中通过促进P53的磷酸化和抑制Bcl2的产生发挥作用，在PBMC中通过抑制P53的磷酸化和增加Bcl2的产生发挥作用。我们的数据首次支持这样的观点，即CIP可能有效地保护正常组织细胞免受辐射损伤，同时在放射治疗中增加癌细胞的死亡。
Ionizing radiation increases cell mortality in a dose-dependent manner. Increases in DNA double strand breaks, γ-H2AX, p53 phophorylation, and protein levels of p53 and Bax also occur. We investigated the ability of ciprofloxacin (CIP), a widely prescribed antibiotic, to inhibit DNA damage induced by ionizing radiation. Human tumor TK6, NH32 (p53−/− of TK6) cells, and human normal peripheral blood mononuclear cells (PBMCs) were exposed to 2–8 Gy 60Co-γ-photon radiation. γ-H2AX (an indicator of DNA strand breaks), phosphorylated p53 (responsible for cell-cycle arrest), Bcl-2, apoptotic proteins, and cell death were measured. Ionizing irradiation increased γ-H2AX amounts in TK6 cells (p53+/+) within 1 hr in a radiation dose-dependent manner. CIP pretreatment and post-treatment effectively inhibited the increase in γ-H2AX. CIP pretreatment reduced Bcl-2 production but promoted p53 phosphorylation, caspase-3 activation and cell death. In NH32 cells, CIP failed to significantly inhibit the radiation-induced γ-H2AX increase, suggesting that CIP inhibition involves in p53-dependent mechanisms. In normal healthy human PBMCs, CIP failed to block the radiation-induced γ-H2AX increase but effectively increased Bcl-2 production but blocked the phospho-p53 increase and subsequent cell death. CIP increased Gadd45α, and enhanced p21 protein 24 hr postirradiation. Results suggest that CIP exerts its effect in TK6 cells by promoting p53 phosphorylation and inhibiting Bcl-2 production and in PBMCs by inhibiting p53 phosphorylation and increasing Bcl-2 production. Our data are the first to support the view that CIP may be effective to protect normal tissue cells from radiation injury, while enhancing cancer cell death in radiation therapy.