Kumar D, Kirshenbaum L, Li T, Danelisen I, Singal P
St. Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Ann N Y Acad Sci. 1999 Jun 30;874:156-68. doi: 10.1111/j.1749-6632.1999.tb09233.x.
Adriamycin (doxorubicin) is a highly potent antineoplastic agent, but its use is limited by the risk of developing cardiomyopathy and congestive heart failure. Available evidence suggests that adriamycin-induced congestive heart failure is mediated by oxidative stress. We examined the possibility of adriamycin-induced apoptosis in isolated adult rat cardiomyocytes and its inhibition by trolox, a water-soluble antioxidant. Cardiomyocytes isolated from rat hearts were exposed to 20 microM adriamycin for 1 h and examined at different post-treatment durations (0-23 h). Adriamycin caused a significant decrease in rod-shaped cells and an increase in round cells. Both Hoechst 33258 staining and TUNEL assay revealed a significantly increased number of apoptotic myocytes and nucleosomal fragmentation upon exposure to adriamycin. In agarose gel electrophoresis, DNA laddering was found to be more intense in adriamycin-exposed myocytes. A bright smear at the leading edge of the gels suggested indiscriminate fragmentation of DNA and myocyte necrosis by adriamycin. Both types of DNA degradations due to adriamycin were significantly reduced by trolox. We suggest that adriamycin-induced cell death involves both apoptosis and necrosis and these may be mediated by oxidative stress.
阿霉素（多柔比星）是一种高效的抗肿瘤药物，但其使用受到发生心肌病和充血性心力衰竭风险的限制。现有证据表明，阿霉素诱导的充血性心力衰竭是由氧化应激介导的。我们研究了阿霉素诱导成年大鼠离体心肌细胞凋亡的可能性以及水溶性抗氧化剂生育三烯酚对其的抑制作用。从大鼠心脏分离的心肌细胞暴露于20微摩尔阿霉素中1小时，并在不同的处理后时间段（0 - 23小时）进行检测。阿霉素导致杆状细胞数量显著减少，圆形细胞数量增加。Hoechst 33258染色和TUNEL检测均显示，暴露于阿霉素后凋亡心肌细胞数量和核小体片段化显著增加。在琼脂糖凝胶电泳中，发现阿霉素处理的心肌细胞中DNA梯状条带更明显。凝胶前沿的明亮拖尾表明阿霉素导致DNA无差别断裂和心肌细胞坏死。生育三烯酚显著减少了阿霉素引起的两种类型的DNA降解。我们认为，阿霉素诱导的细胞死亡涉及凋亡和坏死，且这些可能由氧化应激介导。
