National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center (CMDC), Inje University, Busan 614-735, Korea.
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok 690022, Russia.
Mar Drugs. 2018 Dec 20;17(1):2. doi: 10.3390/md17010002.
Doxorubicin, an anthracycline from , exhibits antitumor activity against various cancers. However, doxorubicin is cardiotoxic at cumulative doses, causing increases in intracellular reactive oxygen species in the heart. Spinochrome D (SpD) has a structure of 2,3,5,6,8-pentahydroxy-1,4-naphthoquinone and is a structural analogue of well-known sea urchin pigment echinochrome A. We previously reported that echinochrome A is cardioprotective against doxorubicin toxicity. In the present study, we assessed the cardioprotective effects of SpD against doxorubicin and determined the underlying mechanism. ¹H-NMR-based metabolomics and mass spectrometry-based proteomics were utilized to characterize the metabolites and proteins induced by SpD in a human cardiomyocyte cell line (AC16) and human breast cancer cell line (MCF-7). Multivariate analyses identified 12 discriminating metabolites (variable importance in projection > 1.0) and 1814 proteins from SpD-treated AC16 cells. Proteomics and metabolomics analyses showed that glutathione metabolism was significantly influenced by SpD treatment in AC16 cells. SpD treatment increased ATP production and the oxygen consumption rate in D-galactose-treated AC16 cells. SpD protected AC16 cells from doxorubicin cytotoxicity, but it did not affect the anticancer properties. With SpD treatment, the mitochondrial membrane potential and mitochondrial calcium localization were significantly different between cardiomyocytes and cancer cell lines. Our findings suggest that SpD could be cardioprotective against the cytotoxicity of doxorubicin.
阿霉素是一种来自 的蒽环类抗生素，对各种癌症具有抗肿瘤活性。然而，阿霉素在累积剂量下具有心脏毒性，导致心脏细胞内活性氧增加。螺旋色酮 D（SpD）的结构为 2,3,5,6,8-五羟基-1,4-萘醌，是著名的海胆色素海胆醌 A 的结构类似物。我们之前报道过海胆醌 A 对阿霉素毒性具有心脏保护作用。在本研究中，我们评估了 SpD 对阿霉素的心脏保护作用，并确定了其潜在机制。我们利用基于 1H-NMR 的代谢组学和基于质谱的蛋白质组学技术，来描述 SpD 在人心肌细胞系（AC16）和人乳腺癌细胞系（MCF-7）中诱导的代谢物和蛋白质。多元分析鉴定出 12 个有区别的代谢物（投影变量重要性 > 1.0）和 SpD 处理的 AC16 细胞中的 1814 种蛋白质。蛋白质组学和代谢组学分析表明，SpD 处理显著影响了 AC16 细胞中的谷胱甘肽代谢。SpD 处理增加了 D-半乳糖处理的 AC16 细胞中的 ATP 产生和耗氧量。SpD 可保护 AC16 细胞免受阿霉素细胞毒性的影响，但不影响抗癌特性。用 SpD 处理后，心肌细胞和癌细胞系之间的线粒体膜电位和线粒体钙定位有明显差异。我们的研究结果表明，SpD 可能对阿霉素的细胞毒性具有心脏保护作用。
