Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde, 06700, Hebei, China.
Department of Radiology, Affiliated Hospital of Chengde Medical University, Chengde, 06700, Hebei, China.
Biomed Pharmacother. 2017 Nov;95:504-512. doi: 10.1016/j.biopha.2017.08.118. Epub 2017 Sep 12.
Doxorubicin (DOX) is a widely used anthracycline derivative anticancer drug, but the use of DOX in clinical applications is limited by its cardiotoxicity. In the current research, we were aiming to assess the effects of Ganoderma lucidum polysaccharides (GLPS) on DOX-induced cardiotoxicity and to illustrate the associated mechanisms. H9c2 rat cardiomyocytes were treated with DOX in the absence or presence of GLPS, and we found GLPS treatment ameliorated DOX-induced H9c2 cell death. Moreover, results of in vivo studies indicated that GLPS significantly decreased the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and aspartate aminotransferase (AST) and attenuated DOX-induced histological changes of the heart tissues. In addition, we found DOX administration promoted myocardial apoptosis, potentiated oxidative stress, decreased the activities of antioxidant enzymes and increased the production of pro-inflammatory cytokines. However, GLPS pretreatment markedly attenuated all these untoward effects of DOX. Furthermore, GLPS pretreatment was found to inhibit Cul3-mediated K48-linked polyubiquitination of Nrf2 through suppressing Cul3 expression, thereby stabilizing Nrf2 expression in H9c2 cells after DOX treatment, leading to the decreased expression of P53 and p-P65 and increased levels of MDM2 and HO-1, resulted in the attenuated apoptosis, oxidative stress and inflammation induced by DOX.
多柔比星（DOX）是一种广泛使用的蒽环类衍生物抗癌药物，但 DOX 在临床应用中的使用受到其心脏毒性的限制。在当前的研究中，我们旨在评估灵芝多糖（GLPS）对 DOX 诱导的心脏毒性的影响，并阐明相关机制。用 DOX 处理 H9c2 大鼠心肌细胞，有无 GLPS 存在，我们发现 GLPS 处理可改善 DOX 诱导的 H9c2 细胞死亡。此外，体内研究结果表明，GLPS 显著降低了血清中乳酸脱氢酶（LDH）、肌酸激酶（CK）和天冬氨酸转氨酶（AST）的水平，并减轻了 DOX 诱导的心脏组织的组织学变化。此外，我们发现 DOX 给药促进心肌细胞凋亡，增强氧化应激，降低抗氧化酶活性，增加促炎细胞因子的产生。然而，GLPS 预处理显著减轻了 DOX 的所有这些不良作用。此外，发现 GLPS 预处理通过抑制 Cul3 表达抑制 Cul3 介导的 Nrf2 的 K48 连接多泛素化，从而稳定 DOX 处理后 H9c2 细胞中 Nrf2 的表达，导致 P53 和 p-P65 的表达减少，MDM2 和 HO-1 的水平增加，从而减轻 DOX 诱导的细胞凋亡、氧化应激和炎症。
