汉防己甲素可减轻顺铂的肾毒性而不降低顺铂的抗肿瘤活性。
Anemoside B4 attenuates nephrotoxicity of cisplatin without reducing anti-tumor activity of cisplatin.
机构信息
Department of Pharmacognosy, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu province 215123, China.
Department of Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
出版信息
Phytomedicine. 2019 Mar 15;56:136-146. doi: 10.1016/j.phymed.2018.10.035. Epub 2018 Oct 31.
BACKGROUND
Cisplatin is a highly effective chemotherapeutic agent commonly used in the treatment of a wide variety of malignancies. However, its clinical usage is severely limited by its serious side effects, especially nephrotoxicity. Anemoside B4, is a major saponins, rich in root of Pulsatilla chinensis (Bunge), has anti-inflammation in vitro. However, the antioxidant or anti-inflammatory effects of anemoside B4 in cisplatin-induced nephrotoxicity have not been clearly demonstrated.
PURPOSE
In this study, we investigated whether anemoside B4 exhibits protective effects against cisplatin-induced nephrotoxicity involving antioxidant or anti-apoptosis effects.
METHOD
To clarify it, the effects of anemoside B4 on HEK 293 cell viability was measured by CCK8 kits, intracellular antioxidant capacity including glutathione reduced (GSH), catalase (CAT) were estimated using chemical kits, apoptosis rate and intracellular reactive oxygen species (ROS) was analyzed by flow cytometry, apoptosis protein was measured by western blotting. In vivo model of cisplatin-induced mice acute renal failure was performed to evaluate the properties of anemoside B4. Besides, to evaluate the effect of anemoside B4 on the anti-tumor activity of cisplatin, S xenograft models were used.
RESULTS
Anemoside B4 potently increased cisplatin-treated HEK 293T cells viability on the concentration and time manners and inhibited cells apoptosis, as demonstrated by the decreased cleaved PARP protein expressions. Anemoside B4 decreased reactive oxygen species (ROS) content and improved superoxide dismutase (SOD) activity. In vivo experiment showed that pretreatment with anemoside B4 effectively adjusted body weight and kidney index, and reduced cisplatin-elevated blood urea nitrogen (BUN) and creatinine (CREA) levels, as well as ameliorated the histopathological damage. Further studies showed that anemoside B4 did not reduce antitumor activity of cisplatin in murine S cancer xenograft tumor models. In addition, anemoside B4 per set showed low toxicity in mice.
CONCLUSION
The strong antioxidant and anti-apoptosis effects of anemoside B4 may provide therapeutic potential for cisplatin-induced nephrotoxicity without compromising its therapeutic efficiency.
背景
顺铂是一种广泛用于治疗多种恶性肿瘤的高效化疗药物。然而，其临床应用受到严重限制，特别是肾毒性。白头翁皂苷 B4 是一种主要的皂苷，富含白头翁根（Bunge），具有体外抗炎作用。然而，白头翁皂苷 B4 在顺铂诱导的肾毒性中的抗氧化或抗炎作用尚未得到明确证实。
目的
在这项研究中，我们研究了白头翁皂苷 B4 是否具有针对顺铂诱导的肾毒性的保护作用，涉及抗氧化或抗细胞凋亡作用。
方法
为了阐明这一点，通过 CCK8 试剂盒测量了白头翁皂苷 B4 对 HEK 293 细胞活力的影响，使用化学试剂盒估计了细胞内抗氧化能力，包括还原型谷胱甘肽（GSH）和过氧化氢酶（CAT），通过流式细胞术分析了细胞凋亡率和细胞内活性氧（ROS），通过蛋白质印迹法测量了凋亡蛋白。在体内顺铂诱导的小鼠急性肾衰竭模型中评估了白头翁皂苷 B4 的性质。此外，为了评估白头翁皂苷 B4 对顺铂抗肿瘤活性的影响，使用了 S 移植瘤模型。
结果
白头翁皂苷 B4 能够在浓度和时间上增强顺铂处理的 HEK 293T 细胞活力，并抑制细胞凋亡，如通过减少裂解的 PARP 蛋白表达所示。白头翁皂苷 B4 降低了活性氧（ROS）含量并提高了超氧化物歧化酶（SOD）活性。体内实验表明，用白头翁皂苷 B4 预处理可有效调节体重和肾脏指数，并降低顺铂升高的血尿素氮（BUN）和肌酐（CREA）水平，以及改善组织病理学损伤。进一步的研究表明，白头翁皂苷 B4 不会降低顺铂在小鼠 S 癌移植瘤模型中的抗肿瘤活性。此外，白头翁皂苷 B4 每组在小鼠中表现出低毒性。
结论
白头翁皂苷 B4 的强大抗氧化和抗细胞凋亡作用可能为顺铂诱导的肾毒性提供治疗潜力，而不影响其治疗效率。
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