Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
Toxicology. 2024 Aug;506:153840. doi: 10.1016/j.tox.2024.153840. Epub 2024 Jun 1.
Cisplatin (CDDP) is administered as an anticancer drug across a broad spectrum of cancer treatments, but it causes severe renal damage. Several studies have attempted to elucidate the cause of CDDP-induced renal injury, but the detailed mechanism remains unclear. We previously found that S3 cells are more sensitive to CDDP than S1 and S2 cells by using immortalized cells derived from S1, S2, and S3 segments of proximal tubules. In this study, we investigated the potential contribution of reactive oxygen species (ROS) to the sensitivity of S3 cells to CDDP. The results showed that S3 cells have high sensitivity to CDDP, paraquat (PQ) and three ROS substances. To examine the mechanisms underlying the sensitivity to ROS in S3 cells, we compared the cellular responses of CDDP- and PQ-exposed S3 cells. The results indicated that the levels of intracellular ROS and lipid peroxides were increased in S3 cells after CDDP and PQ exposure. The intracellular levels of antioxidant proteins such as thioredoxin, thioredoxin reductase 1 and glutathione peroxidase 4 were also increased by exposure to PQ, but these proteins were decreased by CDDP exposure in S3 cells. Furthermore, the levels of intracellular free Fe were increased by CDDP exposure only in S3 cells but not S1 or S2 cells, and cytotoxicity by exposure to CDDP in S3 cells was suppressed by ferroptosis inhibitors. These results suggested that the induction of ferroptosis due to the ROS production through attenuation of the antioxidant system and elevated free Fe is partly responsible for the sensitivity of S3 cells to CDDP.
顺铂 (CDDP) 作为一种抗癌药物广泛应用于各种癌症治疗，但它会导致严重的肾损伤。许多研究试图阐明 CDDP 诱导肾损伤的原因，但详细机制仍不清楚。我们之前使用源自近端小管 S1、S2 和 S3 段的永生化细胞发现，S3 细胞对 CDDP 的敏感性高于 S1 和 S2 细胞。在这项研究中，我们研究了活性氧 (ROS) 对 S3 细胞对 CDDP 敏感性的潜在贡献。结果表明，S3 细胞对 CDDP、百草枯 (PQ) 和三种 ROS 物质高度敏感。为了研究 S3 细胞对 ROS 敏感性的机制，我们比较了 CDDP 和 PQ 暴露的 S3 细胞的细胞反应。结果表明，CDDP 和 PQ 暴露后 S3 细胞内 ROS 和脂质过氧化物的水平增加。PQ 暴露还增加了硫氧还蛋白、硫氧还蛋白还原酶 1 和谷胱甘肽过氧化物酶 4 等抗氧化蛋白的细胞内水平，但这些蛋白在 S3 细胞中被 CDDP 暴露所减少。此外，只有在 S3 细胞中，而不是在 S1 或 S2 细胞中，CDDP 暴露会增加细胞内游离 Fe 的水平，并且 S3 细胞中暴露于 CDDP 的细胞毒性可被铁死亡抑制剂抑制。这些结果表明，由于抗氧化系统减弱和游离 Fe 升高导致 ROS 产生而诱导的铁死亡部分导致了 S3 细胞对 CDDP 的敏感性。
