Liu Wen, Gao Fang-Fang, Li Qun, Lv Jia-Wei, Wang Ying, Hu Peng-Chao, Xiang Qing-Ming, Wei Lei
Department of Pathology and Pathophysiology, Research Center of Food and Drug Evaluation, School of Medicine, Wuhan University, Wuhan, China E-mail :
Asian Pac J Cancer Prev. 2014;15(23):10413-20. doi: 10.7314/apjcp.2014.15.23.10413.
Side effects are an unavoidable consequence of chemotherapy drugs, during which liver injury often takes place. The current study was designed to investigate the protective effect of Astragalus polysaccharides (APS) against the hepatotoxicity induced by frequently-used chemical therapy agents, cyclophosphamide (CTX), docetaxel (DTX) and epirubicin (EPI)) in mice. Mice were divided into five groups, controls, low or high dose groups (DTXL, CTXL, EPIL or DTXH, CTXH, EPIH), and low or high dose chemotherapeutics+APS groups (DTXL+APS, CTXL+APS, EPIL+APS or DTXH+APS, CTXH+APS, EPIH+APS). Controls were treated with equivalent normal saline for 28 days every other day; low or high dose group were intraperitoneal (i.p) injected with low or high doses of CTX, DTX and EPI for 28 days every other day; low or high dose chemotherapeutics+APS group were separately intraperitoneal (i.p) injected with chemotherapeutics for 28 days every other day and i.p with APS (100 mg/kg) for 7 days continually from the 22th to the 28th days. The body weight, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histopathological features, and ultrastructure morphological change of liver tissues, protein expression level of caspase-3 were estimated at different time points. With high dose treatment of DTX, CTX and EPI, weight gain was inhibited and serum levels of ALT and AST were significantly increased. Sections of liver tissue showed massive hepatotoxicity in CTXH group compared to the control group, including hepatic lobule disorder, granular and vacuolar degeneration and necrosis in hepatic cells. These changes were confirmed at ultrastructural level, including obvious pyknosis, heterochromatin aggregation, nuclear membrane resolution, and chondrosome crystal decrease. Western blotting revealed that the protein levels of caspase-3 increased in CTXH group. The low dose groups exhibited trivial hepatotoxicity. More interestingly, after 100 mg/kg APS, liver injury was redecued not only regarding serum transaminase activities (low or high dose chemotherapeutics+APS group), but also from pathological and ultrastructural changes and the protein levels of caspase-3 (CTXH+APS group). In conclusion, DTX, CTX and EPI induce liver damage in a dose dependent manner, whereas APS exerted protective effects.
副作用是化疗药物不可避免的后果，在此过程中常发生肝损伤。本研究旨在探讨黄芪多糖（APS）对常用化疗药物环磷酰胺（CTX）、多西他赛（DTX）和表柔比星（EPI）诱导的小鼠肝毒性的保护作用。将小鼠分为五组，即对照组、低剂量或高剂量组（DTXL、CTXL、EPIL或DTXH、CTXH、EPIH）以及低剂量或高剂量化疗药物+APS组（DTXL+APS、CTXL+APS、EPIL+APS或DTXH+APS、CTXH+APS、EPIH+APS）。对照组每隔一天用等量生理盐水处理28天；低剂量或高剂量组每隔一天腹腔注射低剂量或高剂量的CTX、DTX和EPI，共28天；低剂量或高剂量化疗药物+APS组每隔一天腹腔注射化疗药物28天，并从第22天至第28天连续7天腹腔注射APS（100mg/kg）。在不同时间点评估小鼠体重、血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平、肝组织病理特征、超微结构形态变化以及caspase-3蛋白表达水平。高剂量DTX、CTX和EPI处理后，体重增加受到抑制，血清ALT和AST水平显著升高。与对照组相比，CTXH组肝组织切片显示大量肝毒性，包括肝小叶紊乱、肝细胞颗粒样和空泡样变性及坏死。这些变化在超微结构水平得到证实，包括明显的核固缩、异染色质聚集、核膜溶解和线粒体晶体减少。蛋白质印迹法显示CTXH组caspase-3蛋白水平升高。低剂量组表现出轻微的肝毒性。更有趣的是，给予100mg/kg APS后，不仅血清转氨酶活性方面（低剂量或高剂量化疗药物+APS组）肝损伤减轻，而且在病理和超微结构变化以及caspase-3蛋白水平方面（CTXH+APS组）肝损伤也减轻。总之，DTX、CTX和EPI以剂量依赖性方式诱导肝损伤，而APS发挥了保护作用。
