Role of reactive oxygen species (ROS) in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells.
Role of reactive oxygen species (ROS) in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells.
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发表时间：
2011
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通讯作者：
Xiaohua Gao;D. Deeb;Patrícia Liu;Yongbo Liu;Syed Arbab-Ali;S. Dulchavsky;S. Gautam
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作者：
Xiaohua Gao;D. Deeb;Patrícia Liu;Yongbo Liu;Syed Arbab-Ali;S. Dulchavsky;S. Gautam
CDDO-Me是一种齐墩烷合成的三萜，对包括结直肠癌在内的多种癌症细胞显示出很强的抗肿瘤活性。在本研究中，我们研究了自由基在大肠癌细胞系CDDO-Me生长抑制和诱导凋亡活性中的作用。结果表明，CDDO-Me能有效抑制结直肠癌细胞的生长，用小分子抗氧化剂n -乙酰半胱氨酸（NAC）预处理癌细胞可完全阻断CDDO-Me的生长抑制活性。CDDO-Me引起活性氧的产生，NAC和线粒体链1复合体抑制剂DPI和鱼藤酮抑制了活性氧的产生。CDDO-Me可诱导细胞凋亡，如PARP-1的裂解、procaspase -3、-8和-9的激活以及线粒体去极化和NAC可阻断这些凋亡相关过程的激活。此外，CDDO-Me诱导细胞凋亡与抑制抗凋亡/促存活的Akt、mTOR和NF-kappaB信号蛋白有关，而这些信号分子的抑制作用被NAG阻断。综上所述，这些研究证明CDDO-Me是一种有效的抗癌药物，它通过产生自由基来抑制结直肠癌细胞的生长和凋亡。
CDDO-Me, an oleanane synthetic triterpenoid has shown strong antitumorigeic activity towards diverse cancer cell types including colorectal cancer cells. In the present study, we investigated the role of free radicals in the growth inhibitory and apoptosis-inducing activity of CDDO-Me in colorectal cancer cells lines. Results demonstrated that CDDO-Me potently inhibited the growth of colorectal cancer cells and pretreatment of cancer cells with small-molecule antioxidant N-acetylcysteine (NAC) completely blocked the growth inhibitory activity of CDDO-Me. CDDO-Me caused the generation of reactive oxygen species, which was inhibited by NAC and mitochondrial chain 1 complex inhibitors DPI and rotenone. CDDO-Me induced apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization and NAC blocked the activation of these apoptosis related processes. Furthermore, induction of apoptosis by CDDO-Me was associated with the inhibition of antiapoptotic/ prosurvival Akt, mTOR and NF-kappaB signaling proteins and the inhibition of these signaling molecules was blocked by NAG. Together these studies provided evidence that CDDO-Me is a potent anticancer agent, which imparts growth inhibition and apoptosis in colorectal cancer cells through the generation of free radicals.