Abstract：
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 Fe2+ 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 Fe2+ is partly responsible for the sensitivity of S3 cells to CDDP.
摘要：
顺铂（CDDP）作为抗癌药物在广泛的癌症治疗中使用，但是会导致严重的肾损伤.一些研究试图阐明CDDP诱导的肾损伤的原因，但具体机制尚不清楚.我们先前通过使用源自近端小管的S1，S2和S3段的永生化细胞，发现S3细胞比S1和S2细胞对CDDP更敏感。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具有较高的敏感性，百草枯（PQ）和三种ROS物质。为了检查S3细胞对ROS敏感性的潜在机制，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和脂质过氧化物水平升高。抗氧化蛋白如硫氧还蛋白的细胞内水平，硫氧还蛋白还原酶1和谷胱甘肽过氧化物酶4也因暴露于PQ而增加，但是这些蛋白质在S3细胞中被CDDP暴露减少。此外，CDDP暴露仅在S3细胞而不是S1或S2细胞中增加细胞内游离Fe2+的水平，铁凋亡抑制剂抑制了S3细胞中暴露于CDDP的细胞毒性。这些结果表明，由于抗氧化系统的衰减和游离Fe2的升高导致的ROS产生引起的铁死亡的诱导部分原因是S3细胞对CDDP的敏感性。
