Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, P. R. China.
Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, Hachioji, Japan.
Free Radic Res. 2020 Jan;54(1):64-75. doi: 10.1080/10715762.2019.1703968. Epub 2020 Jan 5.
Bleomycin is a glycopeptide antibiotic that is widely employed in the therapy of a range of lymphomas and germ cell tumours. But the therapeutic efficacy of bleomycin is limited by development of lung fibrosis. The cytotoxicity of bleomycin is mostly ascribed to mitochondrial DNA (mtDNA) damage, while a protective effect of metformin against bleomycin-induced lung fibrosis results from the inhibition of mitochondrial complex I. Since mitochondria and bacteria have certain similarities in structure and function, we used for simplification in the present work to investigate the relationship between metformin and bleomycin with apparently opposite effects on mitochondrial DNA damage. Bleomycin lethality to was ameliorated by metformin treatment accompanying further increase of the level of reactive oxygen species. Catalase but not superoxide dismutases attenuated the protective effect of metformin. Meanwhile, treatment with hydrogen peroxide enhanced the protection, indicating that metformin may protect from bleomycin-induced bactericide enhanced generation of hydrogen peroxide. Moreover, silibinin, a hepatoprotective polyphenolic flavonoid attenuates the cytotoxicity of bleomycin to enhanced generation of hydrogen peroxide as well. This bacterial model in place of mitochondria can provide us with easier screening for the molecules with capability of reducing the bleomycin side effect.
博来霉素是一种糖肽抗生素，广泛应用于多种淋巴瘤和生殖细胞瘤的治疗。但是博来霉素的治疗效果受到肺纤维化的限制。博来霉素的细胞毒性主要归因于线粒体 DNA（mtDNA）损伤，而二甲双胍对博来霉素诱导的肺纤维化的保护作用是通过抑制线粒体复合物 I 实现的。由于线粒体和细菌在结构和功能上具有一定的相似性，我们在本工作中使用 来简化研究二甲双胍和博来霉素之间的关系，它们对线粒体 DNA 损伤有明显相反的作用。二甲双胍治疗可改善博来霉素对 的致死作用，同时进一步增加活性氧的水平。而过氧化氢酶而不是超氧化物歧化酶减弱了二甲双胍的保护作用。同时，用双氧水处理可增强保护作用，表明二甲双胍可能保护 免受博来霉素诱导的杀菌剂 增强的过氧化氢生成。此外，水飞蓟素，一种具有肝保护作用的多酚类黄酮，也可减轻博来霉素对 的细胞毒性，并增强过氧化氢的生成。这种细菌模型代替线粒体，可以为我们提供更容易筛选具有降低博来霉素副作用能力的分子。
