State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, People's Republic of China.
Pharmacol Res. 2013 Apr;70(1):139-46. doi: 10.1016/j.phrs.2013.01.006. Epub 2013 Jan 31.
The cardiotoxicity of adriamycin greatly limits its application in the treatment of cancer. Heart failure that is caused by adriamycin-treatment induced cardiac fibrosis is a major cause of death in patients who are treated with this medication. The severe oxidative stress that is induced by adriamycin is considered to be one of the primary mechanisms by which fibrogenesis of cardiac tissue occurs. In the present study, we demonstrate that 3,3'-diindolymethane (DIM) exhibits a significant anti-fibrosis effect on cardiac tissue in an animal model of adriamycin-induced cardiac fibrosis (AICF). Further studies demonstrated that DIM is able to dramatically up-regulate the expression of breast cancer type 1 susceptibility protein (BRCA1) in cardiac tissue and fibroblast, which subsequently activate the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The upregulation of this transcription factor resulted in the expression of several anti-oxidant genes in the cell. Because DIM is a safe food additive that has been used for decades, our findings suggest that there is a great potential for this chemical to be developed into a clinical medication for the treatment of adriamycin-induced heart failure during cancer therapy.
阿霉素的心脏毒性极大地限制了其在癌症治疗中的应用。阿霉素治疗引起的心脏纤维化导致的心力衰竭是接受这种药物治疗的患者死亡的主要原因。阿霉素诱导的严重氧化应激被认为是心肌组织纤维化发生的主要机制之一。在本研究中，我们证明 3,3'-二吲哚甲烷 (DIM) 在阿霉素诱导的心肌纤维化 (AICF) 动物模型中对心脏组织具有显著的抗纤维化作用。进一步的研究表明，DIM 能够显著上调心脏组织和成纤维细胞中乳腺癌 1 型易感性蛋白 (BRCA1) 的表达，从而激活转录因子核因子 (erythroid-derived 2)-样 2 (Nrf2)。该转录因子的上调导致细胞中几种抗氧化基因的表达。由于 DIM 是一种已安全使用数十年的食品添加剂，我们的研究结果表明，这种化学物质很有潜力被开发成一种用于治疗癌症治疗中阿霉素诱导的心力衰竭的临床药物。
