摘要
顺铂是一种用于化疗的铂制剂,在临床上广泛应用于抗肿瘤治疗。然而由于顺铂所具有的肾毒性和耳毒性以及神经毒性等毒副作用,致使其临床应用受到一定的限制。顺铂损害耳蜗的三个主要靶目标分别是血管纹和毛细胞以及螺旋神经节,这三个靶目标在顺铂的作用下都以细胞凋亡的方式实现其程序化自我毁灭,因此顺铂耳中毒模型是一个典型的内耳细胞凋亡模型。顺铂造成的细胞内氧自由基活动增加和抗氧化酶类的活性丧失是产生细胞损害的重要因素之一,因而抗氧化治疗可有效降低顺铂对耳蜗中上述三个靶目标的破坏程度。顺铂在Caspase(半胱氨酸天冬氨酸蛋白酶)径路上激发的毛细胞凋亡是首先启动Caspase-8的活动,说明毛细胞膜表面的细胞死亡因子受体是顺铂诱导毛细胞凋亡的一根导火索;螺旋神经节细胞的凋亡却是被顺铂同时启动了Caspase-8和Caspase-9,因此螺旋神经节细胞的凋亡不但是因为细胞膜表面的死亡因子受体因受顺铂刺激而发出凋亡的信号,而且还会被从线粒体释放出的细胞色素C启动其凋亡自毁程序。肿瘤抑制基因p53是出现在顺铂耳中毒早期的一个促使细胞凋亡的重要"杀手",应用Superarray技术发现顺铂激发的耳蜗毛细胞和螺旋神经节凋亡基因主要涉及p53,肿瘤坏死因子家族,Death domain family(死亡结构域家族),Bcl-2family,Card family(Caspase相关的招募域家族),和GTP signal transdution(三磷酸鸟苷信号转导)等多条凋亡通路,其中p53信号通路是顺铂诱导毛细胞和螺旋神经节凋亡的主线,因此应用p53抑制剂-Pifithrinα可以通过有效阻止p53的活动而减轻顺铂诱导的毛细胞凋亡。分裂素激活的蛋白激酶在顺铂诱导的内耳细胞凋亡过程中也扮演了重要的角色,应用PD98059可以通过暂时抑制分裂素激活的蛋白激酶活性和p53磷酸化以及Caspase的活动延迟耳蜗毛细胞凋亡的起始阶段,但不能完全阻止病变的扩展,因而PD98059对顺铂引起的耳蜗毛细胞凋亡仅具有短期保护效应。
Cisplatin is an antineoplastic agent that is frequently used for chemotherapeutic treatment of various cancers. However, the clinic application of cisplatin is restricted by its side effects of nephrotoxicity, ototoxicity, and neurotoxicity. Three major targets of cisplatin action in the cochlea are the stria vascularis, the hair cells, and the spiral ganglion neurons. In these regions, the cells die by apoptosis after the cisplatin treatment. Cisplatin treatment increases the production of free radicals and reactive oxygen species, and causes a decline in antioxidant enzymes which can lead to apoptosis by activating caspases, a family of cysteine-aspartate-specific proteases. The treatment of antioxidants therefore can protect cochlear hair cells from cisplatin insult. In the cispaltin-induced caspase apoptotic pathway, caspase-8 is first activated in the hair cells, indicating that the involvement of the death receptor pathway and caspase-8 as the apoptotic initiator in hair cells. In contrast, the spiral ganglion neuron death features the activation of both caspase-8 and caspase-9 at the early stage of the cell death process following the cisplatin treatment. This suggests that the cell death signals in spiral ganglion neurons are released from both the cell death factor receptors on the cell membrane and cytochrome C leakage from the mitochondria, p53, a tumor suppressor gene, is activated in response to DNA damage, stress, and many chemotherapeutic agents including cisplatin, p53 triggers the initiation of cell apoptosis that involves caspase activities in the early stage of cisplatin damage. Using superarray technology, a multiple apoptotic pathways are detected after the cisplatin treatment, including the p53 signaling pathway, tumor necrosis factor receptor superfamily, death domain family, Bcl-2 family, CARD family, and GTP signal transduction. Pifithrin-αis a powerful inhibitor of p53, and greatly enhances hair cell survival from cisplatin damage. Mitogen activated protein kinases also play an important role in cisplatin-induced cell apoptosis. PD98059, an inhibitor of mitogen activated protein kinases, can temporally protect cochlear hair cells by inhibiting the mitogen activated protein kinases, ERK phosphorylations, p53 phospholyrations, and caspase activation. However, the application of PD98059 can only delay the onset of the damage, but can not completely block the progression of the death process.
出处
《中华耳科学杂志》
CSCD
2008年第2期125-133,共9页
Chinese Journal of Otology
