Energy deprivation by silibinin in colorectal cancer cells A double-edged sword targeting both apoptotic and autophagic machineries
Energy deprivation by silibinin in colorectal cancer cells A double-edged sword targeting both apoptotic and autophagic machineries
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DOI：
10.4161/auto.23960
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发表时间：
2013-05-01
期刊：
影响因子：
13.3
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
--
作者：
Raina, Komal;Agarwal, Chapla;Agarwal, Rajesh
具有启动不同类型程序性细胞死亡潜力的小分子可能是有用的辅助疗法，因为当前的抗癌方式由于细胞凋亡机制缺陷或癌细胞对治疗诱导的特定死亡机制的抵抗而无法产生显着的活性。目前的研究首次发现水飞蓟宾是一种天然药物，具有对抗结直肠癌 (CRC) 细胞的双重功效。首先，水飞蓟宾由于活性氧（ROS）的产生以及线粒体电位（（m））的消散和细胞色素c的释放而迅速诱导CRC SW480细胞中的氧化应激，从而导致轻度细胞凋亡作为生物效应。然而，随着水飞蓟宾暴露的增加，细胞内细胞质空泡化加剧，随后细胞器被隔离，从而抑制细胞色素c的进一步释放。有趣的是，细胞凋亡反应的减少与自噬事件的增加相关，通过跟踪细胞内 LC3-II 的动态即可证明这一点。机理研究表明，水飞蓟宾强烈抑制 PIK3CA-AKT-MTOR，但激活 MAP2K1/2-MAPK1/3 通路，从而发挥其生物学作用。水飞蓟宾产生内质网应激，并诱导葡萄糖摄取抑制和能量限制，从而模拟饥饿样条件，证实了这些作用。此外，由于对线粒体代谢、磷脂和蛋白质合成等重要细胞过程的持续干扰，水飞蓟宾对肿瘤细胞的细胞损伤是严重且不可修复的，这表明水飞蓟宾对于结直肠癌细胞来说是一把致命的双刃剑，从而进一步证明了其对抗这种恶性肿瘤的临床有效性。
Small molecules with the potential to initiate different types of programmed cell death could be useful adjunct therapy' where current anticancer modalities fail to generate significant activity due to a defective apoptotic machinery or resistance of cancer cells to the specific death mechanism induced by that treatment. The current study identified silibinin, for the first time, as one such natural agent, having dual efficacy against colorectal cancer (CRC) cells. First, silibinin rapidly induced oxidative stress in CRC SW480 cells due to reactive oxygen species (ROS) generation with a concomitant dissipation of mitchondrial potential ((m)) and cytochrome c release leading to mild apoptosis as a biological effect. However, with increased exposure to silibinin, cytoplasmic vacuolization intensified within the cells followed by sequestration of the organelles, which inhibits the further release of cytochrome c. Interestingly, this decrease in apoptotic response correlated with increased autophagic events as evidenced by tracking the dynamics of LC3-II within the cells. Mechanistic studies revealed that silibinin strongly inhibited PIK3CA-AKT-MTOR but activated MAP2K1/2-MAPK1/3 pathways for its biological effects. Corroborating these effects, endoplasmic reticulum stress was generated and glucose uptake inhibition as well as energy restriction were induced by silibinin, thus, mimicking starvation-like conditions. Further, the cellular damage to tumor cells by silibinin was severe and irreparable due to sustained interference in essential cellular processes such as mitochondrial metabolism, phospholipid and protein synthesis, suggesting that silibinin harbors a deadly double-edged sword' against CRC cells thereby further advocating its clinical effectiveness against this malignancy.