Department of Biological Sciences, Federal University of São Paulo, Diadema Campus, Diadema, SP, Brazil.
Cancer Chemother Pharmacol. 2010 Apr;65(5):989-94. doi: 10.1007/s00280-010-1244-x. Epub 2010 Jan 28.
Anthracyclines have been widely used as antitumor agents, playing a crucial role in the successful treatment of many types of cancer, despite some side effects related to cardiotoxicity. New anthracyclines have been designed and tested, but the first ones discovered, doxorubicin and daunorubicin, continue to be the drugs of choice. Despite their extensive use in chemotherapy, little is known about the DNA repair mechanisms involved in the removal of lesions caused by anthracyclines. The anthracycline cosmomycin D is the main product isolated from Streptomyces olindensis, characterized by a peculiar pattern of glycosylation with two trisaccharide rings attached to the A ring of the tetrahydrotetracene.
We assessed the induction of apoptosis (Sub-G1) by cosmomycin D in nucleotide excision repair-deficient fibroblasts (XP-A and XP-C) as well as the levels of DNA damage (alkaline comet assay).
Treatment of XP-A and XP-C cells with cosmomycin D resulted in apoptosis in a time-dependent manner, with highest apoptosis levels observed 96 h after treatment. The effects of cosmomycin D were equivalent to those obtained with doxorubicin. The broad caspase inhibitor Z-VAD-FMK strongly inhibited apoptosis in these cells, and DNA damage induced by cosmomycin D was confirmed by alkaline comet assay.
Cosmomycin D induced time-dependent apoptosis in nucleotide excision repair-deficient fibroblasts. Despite similar apoptosis levels, cosmomycin D caused considerably lower levels of DNA damage compared to doxorubicin. This may be related to differences in structure between cosmomycin D and doxorubicin.
蒽环类药物已被广泛用作抗肿瘤药物，在成功治疗许多类型的癌症方面发挥了关键作用，尽管其存在一些与心脏毒性相关的副作用。新的蒽环类药物已经被设计和测试，但最初发现的多柔比星和柔红霉素仍然是首选药物。尽管它们在化疗中广泛使用，但对于涉及蒽环类药物引起的损伤清除的 DNA 修复机制知之甚少。蒽环类抗生素 cosmomycin D 是从链霉菌（Streptomyces olindensis）中分离得到的主要产物，其特征是具有两个三糖环连接到四环四氢的 A 环的独特糖基化模式。
我们评估了 cosmomycin D 在核苷酸切除修复缺陷型成纤维细胞（XP-A 和 XP-C）中诱导细胞凋亡（Sub-G1）的情况，以及 DNA 损伤水平（碱性彗星试验）。
cosmomycin D 处理 XP-A 和 XP-C 细胞会导致细胞凋亡，且呈时间依赖性，处理 96 小时后观察到最高的凋亡水平。 cosmomycin D 的作用与多柔比星相当。广谱半胱天冬酶抑制剂 Z-VAD-FMK 强烈抑制这些细胞的凋亡，并且通过碱性彗星试验证实 cosmomycin D 诱导的 DNA 损伤。
cosmomycin D 可诱导核苷酸切除修复缺陷型成纤维细胞的时间依赖性凋亡。尽管凋亡水平相似，但 cosmomycin D 引起的 DNA 损伤水平明显低于多柔比星。这可能与 cosmomycin D 和多柔比星的结构差异有关。
