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首页> 外文期刊>Apoptosis >Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism
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Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism

机译：羟自由基通过Bcl-2依赖性机制介导顺铂诱导的人毛囊真皮乳头细胞和角质形成细胞凋亡

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摘要

Induction of massive apoptosis of hair follicle cells by chemotherapy has been implicated in the pathogenesis of chemotherapy-induced alopecia (CIA), but the underlying mechanisms of regulation are not well understood. The present study investigated the apoptotic effect of cisplatin in human hair follicle dermal papilla cells and HaCaT keratinocytes, and determined the identity and role of specific reactive oxygen species (ROS) involved in the process. Treatment of the cells with cisplatin induced ROS generation and a parallel increase in caspase activation and apoptotic cell death. Inhibition of ROS generation by antioxidants inhibited the apoptotic effect of cisplatin, indicating the role of ROS in the process. Studies using specific ROS scavengers further showed that hydroxyl radical, but not hydrogen peroxide or superoxide anion, is the primary oxidative species responsible for the apoptotic effect of cisplatin. Electron spin resonance studies confirmed the formation of hydroxyl radicals induced by cisplatin. The mechanism by which hydroxyl radical mediates the apoptotic effect of cisplatin was shown to involve down-regulation of the anti-apoptotic protein Bcl-2 through ubiquitin-proteasomal degradation. Bcl-2 was also shown to have a negative regulatory role on hydroxyl radical. Together, our results indicate an essential role of hydroxyl radical in cisplatin-induced cell death of hair follicle cells through Bcl-2 regulation. Since CIA is a major side effect of cisplatin and many other chemotherapeutic agents with no known effective treatments, the knowledge gained from this study could be useful in the design of preventive treatment strategies for CIA through localized therapy without compromising the chemotherapy efficacy.
机译：化学疗法诱导毛囊细胞大量凋亡与化学疗法诱发的脱发症（CIA）的发病机制有关，但尚不清楚其调控的基本机制。本研究调查了顺铂在人毛囊真皮乳头细胞和HaCaT角质形成细胞中的凋亡作用，并确定了参与该过程的特定活性氧（ROS）的身份和作用。用顺铂处理细胞会诱导ROS生成，并同时增加caspase激活和凋亡细胞死亡。抗氧化剂抑制ROS的产生可抑制顺铂的凋亡作用，表明ROS在此过程中的作用。使用特定的ROS清除剂进行的研究进一步表明，羟自由基（而不是过氧化氢或超氧阴离子）是负责顺铂凋亡作用的主要氧化物质。电子自旋共振研究证实了顺铂诱导的羟基自由基的形成。羟基自由基介导顺铂凋亡作用的机制显示出通过泛素-蛋白酶体降解下调抗凋亡蛋白Bcl-2的作用。还显示了Bcl-2对羟基自由基具有负调节作用。总之，我们的结果表明，通过Bcl-2调节，羟基自由基在顺铂诱导的毛囊细胞死亡中具有重要作用。由于CIA是顺铂和许多其他化疗药物的主要副作用，尚无有效的治疗方法，因此，从这项研究中获得的知识可用于通过局部治疗设计CIA的预防性治疗策略，而不会影响化学疗法的疗效。

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