Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Neurobiol Dis. 2011 Mar;41(3):661-8. doi: 10.1016/j.nbd.2010.11.017. Epub 2010 Dec 8.
Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral neuropathy in 30% of patients. Peripheral neuropathy is the dose limiting side effect, which has no preventative therapy. We have previously shown that cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by covalently binding to nuclear DNA (nDNA), resulting in DNA damage, subsequent p53 activation and Bax-mediated apoptosis via the mitochondria. We now demonstrate that cisplatin also directly binds to mitochondrial DNA (mtDNA) with the same binding affinity as nDNA. Cisplatin binds 1 platinum molecule per 2166 mtDNA base pairs and 1 platinum molecule per 3800 nDNA base pairs. Furthermore, cisplatin treatment inhibits mtDNA replication as detected by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and inhibits transcription of mitochondrial genes. The relative reduction in mtDNA transcription is directly related to the distance the gene is located from the transcription initiation point, which implies that randomly formed platinum adducts block transcription. Cisplatin treated DRG neurons exhibit mitochondrial vacuolization and degradation in vitro and in vivo. Taken together, this data suggests that direct mtDNA damage may provide a novel, distinct mechanism for cisplatin-induced neurotoxicity separate from the established nDNA damage pathway.
顺铂是一种基于铂的化疗药物，它会导致 30%的患者出现周围神经病变。周围神经病变是剂量限制的副作用，目前尚无预防疗法。我们之前已经表明，顺铂通过与核 DNA（nDNA）共价结合，导致 DNA 损伤，随后通过线粒体激活 p53 和 Bax 介导的细胞凋亡，从而诱导背根神经节（DRG）感觉神经元凋亡。现在我们证明顺铂也可以直接与线粒体 DNA（mtDNA）结合，其结合亲和力与 nDNA 相同。顺铂每 2166 个 mtDNA 碱基对结合 1 个铂分子，每 3800 个 nDNA 碱基对结合 1 个铂分子。此外，顺铂处理可抑制 mtDNA 复制，如 5-溴-2'-脱氧尿苷（BrdU）掺入所检测到的，并且抑制线粒体基因的转录。mtDNA 转录的相对减少与基因距转录起始点的距离直接相关，这意味着随机形成的铂加合物会阻止转录。顺铂处理的 DRG 神经元在体外和体内表现出线粒体空泡化和降解。综上所述，这些数据表明，直接的 mtDNA 损伤可能为顺铂诱导的神经毒性提供一种新颖而独特的机制，与已建立的 nDNA 损伤途径不同。
