Cysteine-conjugated metabolites of ginger components, shogaols, induce apoptosis through oxidative stress-mediated p53 pathway in human colon cancer cells.
Cysteine-conjugated metabolites of ginger components, shogaols, induce apoptosis through oxidative stress-mediated p53 pathway in human colon cancer cells.
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DOI：
10.1021/jf501351r
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发表时间：
2014-05-21
影响因子：
6.1
通讯作者：
Sang S
中科院分区：
文献类型：
--
作者：
Fu J;Chen H;Soroka DN;Warin RF;Sang S
姜辣素是热加工生姜的主要成分，已被证明是高效的抗癌剂。我们的团队已经确定半胱氨酸结合的shogaol(M2、M2‘和M2“)是[6]-、[8]-和[10]-shogaol在人类中的主要代谢物，并发现M2是其母分子[6]-shogaol在癌细胞和小鼠中的载体，而对正常结肠成纤维细胞的毒性较小。本研究的目的是确定M2‘和M2“作为抗癌药物在代谢和疗效方面是否与M2相似，并进一步探讨半胱氨酸偶联的shogaol对人结肠癌细胞HCT-116和HT-29的生物促凋亡机制。我们的结果表明，[8]-和[10]-shogaol具有与[6]-shogaol相似的代谢特征，并且对人结肠癌细胞表现出类似的毒性。M2‘和M2“对正常结肠细胞都表现出低毒，但对结肠癌细胞保持效力，这表明它们具有与M2相似的活性。我们进一步证明，半胱氨酸偶联的shogaol可以通过激活线粒体凋亡途径导致癌细胞死亡。我们的结果表明，氧化应激激活了一条P53通路，最终导致PUMA诱导和下调B细胞淋巴瘤2(Bcl2)的PUMA表达，随后细胞色素c的释放，X连锁的凋亡抑制蛋白(XIAP)与caspase的抑制相互作用的扰动，最终导致caspase 9和caspase 3的激活和切割。对M2促凋亡活性减弱的标记物的简要筛选显示，[8]和[10]-shogaol及其各自的半胱氨酸偶联代谢物M2‘和M2“的结果相似。这项研究强调了Shogaol的半胱氨酸结合的代谢物作为新的饮食结肠癌预防药物。
Shogaols, the major constituents of thermally processed ginger, have been proven to be highly effective anticancer agents. Our group has identified cysteine-conjugated shogaols (M2, M2′, and M2″) as the major metabolites of [6]-, [8]-, and [10]-shogaol in human and found that M2 is a carrier of its parent molecule [6]-shogaol in cancer cells and in mice, while being less toxic to normal colon fibroblast cells. The objectives of this study are to determine whether M2′ and M2″ behave in a similar manner to M2, in both metabolism and efficacy as anticancer agents, and to further explore the biological pro-apoptotic mechanisms of the cysteine-conjugated shogaols against human colon cancer cells HCT-116 and HT-29. Our results show that [8]- and [10]-shogaol have similar metabolic profiles to [6]-shogaol and exhibit similar toxicity toward human colon cancer cells. M2′ and M2″ both show low toxicity against normal colon cells but retain potency against colon cancer cells, suggesting that they have similar activity to M2. We further demonstrate that the cysteine-conjugated shogaols can cause cancer cell death through the activation of the mitochondrial apoptotic pathway. Our results show that oxidative stress activates a p53 pathway that ultimately leads to p53 up-regulated modulator of apoptosis (PUMA) induction and down-regulation of B-cell lymphoma 2 (Bcl-2), followed by cytochrome c release, perturbation of inhibitory interactions of X-linked inhibitor of apoptosis protein (XIAP) with caspases, and finally caspase 9 and 3 activation and cleavage. A brief screen of the markers attenuated by the proapoptotic activity of M2 revealed similar results for [8]- and [10]-shogaol and their respective cysteine-conjugated metabolites M2′ and M2″. This study highlights the cysteine-conjugated metabolites of shogaols as novel dietary colon cancer preventive agents.
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姜的6个shogaol提取物上调细胞和小鼠的抗氧化剂防御系统。
DOI：
10.3390/molecules17078037
发表时间：
2012-07-04
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bak MJ;Ok S;Jun M;Jeong WS
通讯作者：
Jeong WS
DOI：
10.1016/j.jchromb.2012.09.020
发表时间：
2012-10-15
影响因子：
3
作者：
Chen, Huadong;Sang, Shengmin
通讯作者：
Sang, Shengmin
影响因子：
3.9
作者：
Chen, Huadong;Lv, Lishuang;Sang, Shengmin
通讯作者：
Sang, Shengmin
影响因子：
4.1
作者：
Conaway, CC;Krzeminski, J;Chung, FL
通讯作者：
Chung, FL
影响因子：
4.1
作者：
Chen, Huadong;Soroka, Dominique N.;Sang, Shengmin
通讯作者：
Sang, Shengmin