Ma Liwei, Wang Hongjun, Wang Chunyan, Su Jing, Xie Qi, Xu Lu, Yu Yang, Liu Shibing, Li Songyan, Xu Ye, Li Zhixin
1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China; 2Department of Histology and Embryology, Jilin Medical University, Jilin 132013, China.
Aging Dis. 2016 May 27;7(3):254-66. doi: 10.14336/AD.2016.0118. eCollection 2016 May.
Cisplatin is a commonly used chemotherapeutic drug, used for the treatment of malignant ovarian cancer, but acquired resistance limits its application. There is therefore an overwhelming need to understand the mechanism of cisplatin resistance in ovarian cancer, that is, ovarian cancer cells are insensitive to cisplatin treatment. Here, we show that failure of elevating calcium and oxidative stress tolerance play key roles in cisplatin resistance in ovarian cancer cell lines. Cisplatin induces an increase in oxidative stress and alters intracellular Ca(2+) concentration, including cytosolic and mitochondrial Ca(2+) in cisplatin-sensitive SKOV3 cells, but not in cisplatin-resistant SKOV3/DDP cells. Cisplatin induces mitochondrial damage and triggers the mitochondrial apoptotic pathway in cisplatin-sensitive SKOV3 cells, but rarely in cisplatin-resistant SKOV3/DDP cells. Inhibition of calcium signaling attenuates cisplatin-induced oxidative stress and intracellular Ca(2+) overload in cisplatin-sensitive SKOV3 cells. Moreover, in vivo xenograft models of nude mouse, cisplatin significantly reduced the growth rates of tumors originating from SKOV3 cells, but not that of SKOV3/DDP cells. Collectively, our data indicate that failure of calcium up-regulation mediates cisplatin resistance by alleviating oxidative stress in ovarian cancer cells. Our results highlight potential therapeutic strategies to improve cisplatin resistance.
顺铂是一种常用的化疗药物，用于治疗恶性卵巢癌，但获得性耐药限制了其应用。因此，迫切需要了解卵巢癌中顺铂耐药的机制，即卵巢癌细胞对顺铂治疗不敏感。在此，我们表明钙升高失败和氧化应激耐受性在卵巢癌细胞系的顺铂耐药中起关键作用。顺铂可诱导氧化应激增加并改变细胞内Ca(2+)浓度，包括顺铂敏感的SKOV3细胞中的胞质和线粒体Ca(2+)，但在顺铂耐药的SKOV3/DDP细胞中则不然。顺铂可诱导顺铂敏感的SKOV3细胞中的线粒体损伤并触发线粒体凋亡途径，但在顺铂耐药的SKOV3/DDP细胞中很少见。抑制钙信号可减轻顺铂敏感的SKOV3细胞中顺铂诱导的氧化应激和细胞内Ca(2+)过载。此外，在裸鼠体内异种移植模型中，顺铂显著降低了源自SKOV3细胞的肿瘤生长速度，但对SKOV3/DDP细胞则不然。总体而言，我们的数据表明钙上调失败通过减轻卵巢癌细胞中的氧化应激来介导顺铂耐药。我们的结果突出了改善顺铂耐药的潜在治疗策略。
