Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Phytomedicine. 2022 Aug;103:154213. doi: 10.1016/j.phymed.2022.154213. Epub 2022 May 29.
Chinese herbal medicine has been developed as the traditional Japanese Kampo medicine, and it has been widely used to cure various symptoms in clinical practice. However, only a few studies are currently available on the effect of the Kampo medicine on renal disease. Nephrotoxicity is one of major side effect of cisplatin, the first metal-based anticancer drug. In the present study, we examined the effect of the Kampo medicine against cisplatin-induced nephrotoxicity (CIN).
First, we screened the ethical Kampo extract formulation having positive effect against CIN using HK-2 cells. Next, we examined the preventive action of the selected ethical Kampo extract formulation against CIN in vivo using a mouse model.
Cisplatin-induced cell death was significantly suppressed by TJ-43 (Rikkunshito) and TJ-90 (Seihaito); however, cisplatin-induced cleaved caspase-3 expression was inhibited only by TJ-90. In an in vivo mouse model of cisplatin-induced kidney injury with dysfunction and increased inflammatory cytokine expression, TJ-90 showed amelioration of these damaging effects. Cisplatin-induced apoptosis and superoxide production were inhibited by treatment with TJ-90. The expression of cleaved caspase-3, 4-hydroxynonenal, and MAPK phosphorylation increased after cisplatin administration, but decreased after the administration of TJ-90. Among 16 crude drug extracts present in Seihaito, Bamboo Culm (Chikujo in Japanese) inhibited cisplatin-induced cell death and cleaved caspase-3 expression in HK-2 cells. Moreover, the anti-tumor effect of cisplatin was not affected by TJ-90 co-treatment in cancer cell lines.
TJ-90 might have a novel preventive action against CIN through the suppression of inflammation, apoptosis, and oxidative stress without interfering with the anti-tumor effect of cisplatin. Collectively, these findings might contribute to innovations in supportive care for cancer treatment-related side effects.
中药已被开发为传统的日本汉方药，并在临床实践中广泛用于治疗各种症状。然而，目前关于汉方药对肾病影响的研究较少。顺铂是第一种金属基抗癌药物，其肾毒性是其主要的副作用之一。在本研究中，我们研究了汉方药对顺铂诱导的肾毒性（CIN）的作用。
首先，我们使用 HK-2 细胞筛选对 CIN 有积极作用的伦理汉方药提取物配方。接下来，我们使用小鼠模型研究所选伦理汉方药提取物配方对 CIN 的预防作用。
TJ-43（六君子汤）和 TJ-90（柴苓汤）显著抑制顺铂诱导的细胞死亡；然而，只有 TJ-90 抑制了顺铂诱导的半胱天冬酶-3 的表达。在顺铂诱导的肾功能障碍和炎症细胞因子表达增加的小鼠肾脏损伤模型中，TJ-90 改善了这些损伤作用。TJ-90 抑制了顺铂诱导的细胞凋亡和超氧化物的产生。顺铂给药后，cleaved caspase-3、4-羟基壬烯醛和 MAPK 磷酸化的表达增加，但 TJ-90 给药后减少。在柴苓汤中存在的 16 种生药提取物中，竹茹（日文：竹笥）抑制了 HK-2 细胞中顺铂诱导的细胞死亡和 cleaved caspase-3 的表达。此外，TJ-90 共处理对癌细胞系中顺铂的抗肿瘤作用没有影响。
TJ-90 可能通过抑制炎症、凋亡和氧化应激来预防 CIN，而不干扰顺铂的抗肿瘤作用。总之，这些发现可能为癌症治疗相关副作用的支持性护理创新做出贡献。
