Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems
Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems
复制标题
DOI：
10.1016/j.canlet.2019.02.034
复制
发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
De Ridder, Mark
中科院分区：
文献类型：
--
作者：
Wang, Hui;Jiang, Heng;De Ridder, Mark
辣椒素（PL）是辣椒中天然合成的一种抗肿瘤药物，能通过干扰活性氧（ROS）的体内平衡选择性地杀死肿瘤细胞。ROS是辐射的主要效应分子，已知通过药理学调节增加ROS产生可增强辐射应答。因此，我们研究了PL在结直肠癌细胞（CT 26和DLD-1）和CT 26荷瘤小鼠中的放射增敏作用。首先，我们发现，PL诱导过量的ROS的产生，由于耗尽谷胱甘肽和硫氧还蛋白还原酶的抑制。其次，PL增强了肿瘤细胞的内在和缺氧辐射敏感性，与ROS介导的DNA损伤增加，G2/M细胞周期阻滞和细胞呼吸抑制有关。最后，在体内验证了PL的放射增敏作用。PL能改善肿瘤对单次和分次照射的反应，显著提高荷瘤小鼠的生存率，但单独使用PL无效。与体外研究结果一致，增强的放射反应与抗氧化系统的抑制有关。总之，我们的研究结果表明，PL可能是一个潜在的放射增敏剂在结直肠癌。
Piperlongumine (PL), naturally synthesized in long pepper, is known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis. ROS are the primary effector molecules of radiation, and increase of ROS production by pharmacological modulation is known to enhance radioresponse. We therefore investigated the radiosensitizing effect of PL in colorectal cancer cells (CT26 and DLD-1) and CT26 tumor-bearing mice. Firstly, we found that PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase. Secondly, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells, linked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration. Finally, the radiosensitizing effect of PL was verified in vivo. PL improved the tumor response to both single and fractionated radiation, resulting in a significant increase of survival rate of tumor-bearing mice, while it was ineffective on its own. In line with in vitro findings, enhanced radioresponse is associated with inhibition of antioxidant systems. In conclusion, our results suggest that PL could be a potential radiosensitizer in colorectal cancer.