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Ascorbyl stearate and ionizing radiation potentiate apoptosis through intracellular thiols and oxidative stress in murine T lymphoma cells
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2017-12-19 , DOI: 10.1016/j.cbi.2017.12.028
Shirish D. Mane , Akhilender Naidu Kamatham

Ascorbyl stearate (Asc-s) is a derivative of ascorbic acid with better anti-tumour efficacy compared to its parent compound ascorbic acid. In this study, we have examined radio-sensitizing effect of Asc-s in murine T cell lymphoma (EL4) cells at 4 Gy. Asc-s and radiation treatment reduced cell proliferation, induced apoptosis in a dose dependent manner by arresting the cells at S/G2-M phase of cell cycle. It also decreased the frequency of cancer stem cells per se, with significantly higher decrease in combination with radiation treatment./Further, Asc-s and radiation treatment increased the level of reactive oxygen species (ROS), drop in mitochondrial membrane potential (MMP) and increased caspase-3 activity resulting in apoptosis of EL4 cells. Further it also significantly decreased GSH/GSSG ratio due to binding of Asc-s with thiols. The increase in oxidative stress induced by Asc-s and radiation treatment was abrogated by thiol antioxidants in EL4 cells. Interestingly, this redox modulation triggered significant increase in protein glutathionylation in a time dependent manner. Asc-s treatment resulted in glutathionylation of IKK, p50-NF-kB and mutated p53, thereby inhibiting cancer progression during oxidative stress. Asc-s quenches GSH ensuing Asc-s + GSH adduct thereby further modulating GSH/GSSG ratio as evident from HPLC and docking studies. The anti-tumour effect of Asc-s along with radiation was studied by injecting EL4 cells in synegenicC57/BL6 male mice. Intraperitoneal injection of Asc-s followed by radiation exposure at 4 Gy to the tumour bearing mice resulted in radio-sensitization which is evident from significant regression of tumour as evident from tumour burden index. The survival study supports the data that Asc-s pre-treatment enhances radio-sensitization in murine lymphoma. Our data, suggest that Asc-s and ionizing radiation induced cell cycle arrest and apoptosis by perturbing redox balance through irreversible complexes of thiols with Asc-s, disturbed mitochondrial membrane permeability and activation of caspase-3 in EL4 cells.



中文翻译:

硬脂酸抗坏血酸和电离辐射通过小鼠T淋巴瘤细胞内的硫醇和氧化应激增强细胞凋亡

硬脂酸抗坏血酸酯(Asc-s)是抗坏血酸的衍生物,与其母体化合物抗坏血酸相比具有更好的抗肿瘤功效。在这项研究中,我们检查了Asc-s在4 Gy浓度下对鼠T细胞淋巴瘤(EL4)细胞的放射增敏作用。Asc-s和放射治疗通过将细胞停滞在细胞周期的S / G2-M期,以剂量依赖的方式减少细胞增殖,诱导凋亡。它也降低了癌症干细胞本身的频率,与放射治疗相结合的降低幅度明显更高。/进一步,Asc-s和放射治疗增加了活性氧(ROS)的水平,线粒体膜电位(MMP)的下降和增加的caspase-3活性导致EL4细胞凋亡。此外,由于Asc-s与硫醇的结合,它也显着降低了GSH / GSSG比。由Asc-s和辐射处理引起的氧化应激的增加被EL4细胞中的硫醇抗氧化剂所消除。有趣的是,这种氧化还原调节以时间依赖性方式触发了蛋白质谷胱甘肽酰化的显着增加。Asc-s治疗导致IKK,p50-NF-kB和突变的p53的谷胱甘肽酰化,从而抑制了氧化应激期间的癌症进展。Asc-s可淬灭随后的Asc-s + GSH加合物的GSH,从而进一步调节GSH / GSSG的比值,这在HPLC和对接研究中很明显。通过在同基因的C57 / BL6雄性小鼠中注射EL4细胞,研究了Asc-s与放射线的抗肿瘤作用。腹膜内注射Asc-s,然后以4 Gy的剂量将放射线照射到荷瘤小鼠身上,导致放射增敏,这从肿瘤的明显消退可以明显看出,从肿瘤负荷指数也可以看出。生存研究支持Asc-s预处理增强鼠淋巴瘤放射敏感性的数据。我们的数据表明,Asc-s和电离辐射通过干扰不可逆的硫醇与Asc-s的复合物扰动氧化还原平衡,扰乱线粒体膜通透性和激活EL4细胞中的caspase-3来诱导细胞周期停滞和凋亡。

更新日期:2017-12-19
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