Emergency Resuscitation Center, Department of Medicine, University of Chicago, IL 60637, USA.
Am J Chin Med. 2010;38(3):569-84. doi: 10.1142/S0192415X10008068.
Doxorubicin (Dox) is one of the most widely used and successful chemotherapeutic antitumor drugs. Its clinical application is highly limited due to its cumulative dose-related cardiotoxicity. Proposed mechanisms include the generation of reactive oxygen species (ROS)-mediated oxidative stress. Therefore, reducing oxidative stress should be protective against Dox-induced cardiotoxicity. To determine whether antioxidant, grape seed proanthocyanidin extract (GSPE) attenuates Dox-induced ROS generation and protects cardiomyocytes from Dox-induced oxidant injury, cultured primary cardiomyocytes were treated with doxorubicin (Dox, 10 microM) alone or GSPE (50 microg/ml) with Dox (10 microM) for 24 hours. Dox increased intracellular ROS production as measured by 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, induced significant cell death as assessed by propidium iodide, and declined the redox ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) and disrupted mitochondrial membrane potential as determined by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethlbenzimidazole-carbocyanide iodine (JC-1). Analysis of agarose gel electrophoresis revealed Dox-induced nuclear DNA damage with the ladder like fragmentation. GSPE treatment suppressed those alterations. Electron Spin Resonance (ESR) spectroscopy data also showed that GSPE strongly scavenged hydroxyl radical, superoxide and DPPH radicals. Together, these findings indicate that GSPE in combination with Dox has protective effect against Dox-induced toxicity in cardiomyocytes, which may be in part attributed to its antioxidative activity. Importantly, flow cytometric analysis demonstrated that co-treatment of Dox and GSPE did not decrease the proliferation-inhibitory effect of Dox in MCF-7 human breast carcinoma cells. Thus, GSPE may be a promising adjuvant to prevent cardiotoxicity without interfering with antineoplastic activity during chemotherapeutic treatment with Dox.
多柔比星（Dox）是最广泛使用和最成功的化学抗肿瘤药物之一。由于其累积剂量相关的心脏毒性，其临床应用受到高度限制。提出的机制包括活性氧物种（ROS）介导的氧化应激的产生。因此，减少氧化应激应该对多柔比星诱导的心脏毒性具有保护作用。为了确定抗氧化剂，葡萄籽原花青素提取物（GSPE）是否减轻多柔比星诱导的 ROS 生成并保护心肌细胞免受多柔比星诱导的氧化剂损伤，用多柔比星（Dox，10 μM）单独或 Dox（10 μM）与 GSPE（50μg/ml）处理培养的原代心肌细胞 24 小时。多柔比星通过 6-羧基-2'，7'-二氯二氢荧光素二乙酸酯测量增加细胞内 ROS 生成，通过碘化丙啶评估诱导显著的细胞死亡，并降低还原型谷胱甘肽（GSH）/氧化型谷胱甘肽（GSSG）的氧化还原比和破坏线粒体膜电位如 5,5',6,6'-四氯-1,1',3,3'-四乙基苯并咪唑 - 碳化二亚胺碘化物（JC-1）所测定。琼脂糖凝胶电泳分析显示多柔比星诱导核 DNA 损伤具有梯状片段化。GSPE 处理抑制了这些改变。电子自旋共振（ESR）光谱数据也表明 GSPE 强烈清除羟基自由基，超氧自由基和 DPPH 自由基。总之，这些发现表明，GSPE 与多柔比星联合使用对心肌细胞中多柔比星诱导的毒性具有保护作用，这可能部分归因于其抗氧化活性。重要的是，流式细胞术分析表明，多柔比星和 GSPE 的共同处理不会降低多柔比星在 MCF-7 人乳腺癌细胞中的增殖抑制作用。因此，GSPE 可能是一种有前途的佐剂，可预防心脏毒性，而不会干扰多柔比星化疗期间的抗肿瘤活性。
