Halocynthiaxanthin and Peridinin Sensitize Colon Cancer Cell Lines to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand
Halocynthiaxanthin and Peridinin Sensitize Colon Cancer Cell Lines to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand
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DOI：
10.1158/1541-7786.mcr-06-0045
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发表时间：
2007-06
影响因子：
5.2
通讯作者：
Tatsushi Yoshida;T. Maoka;Swadesh K. Das;K. Kanazawa;Mano Horinaka;Miki Wakada;Y. Satomi;H. Nishino;T. Sakai
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文献类型：
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作者：
Tatsushi Yoshida;T. Maoka;Swadesh K. Das;K. Kanazawa;Mano Horinaka;Miki Wakada;Y. Satomi;H. Nishino;T. Sakai
类胡萝卜素是食物中含有的化合物，具有抗癌活性。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）具有选择性诱导肿瘤细胞凋亡的作用，是一种很有前途的肿瘤治疗药物。然而，一些肿瘤仍然耐受TRAIL诱导的细胞凋亡。因此，重要的是开发克服这种耐药性的药物。我们首次发现，某些类胡萝卜素使癌细胞对TRAIL诱导的凋亡敏感。与halocynthiaxanthin，牡蛎和海葵中含有的膳食类胡萝卜素，和TRAIL的联合治疗大大诱导结肠癌DLD-1细胞的凋亡，而每种药物单独只轻微诱导凋亡。该组合诱导细胞核浓缩和聚（ADP-核糖）聚合酶裂解，这是细胞凋亡的主要特征。各种caspase抑制剂可以减弱这种组合诱导的细胞凋亡。此外，显性负性形式的TRAIL受体可以阻断细胞凋亡，表明卤氰噻黄质特异性地促进TRAIL信号通路。为了研究联合治疗的协同作用的分子机制，我们进行了RNA酶保护测定。在死亡受体相关基因中，盐芥黄素显著上调TRAIL受体死亡受体5（DR 5），提示了联合作用的可能机制。此外，我们还研究了其他类胡萝卜素是否也具有相同的效果。Peridinin，而不是四黄质，diadinochrome，和pyrrhoxanthin，诱导DR 5的表达和敏化DLD-1细胞TRAIL诱导的凋亡。这些结果表明，某些类胡萝卜素和TRAIL的组合是克服癌细胞中TRAIL抗性的新策略。(Mol Cancer Res 2007;5（6）：615-25）
Carotenoids are compounds contained in foods and possess anticarcinogenic activity. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. However, some tumors remain tolerant to TRAIL-induced apoptosis. Therefore, it is important to develop agents that overcome this resistance. We show, for the first time, that certain carotenoids sensitize cancer cells to TRAIL-induced apoptosis. Combined treatment with halocynthiaxanthin, a dietary carotenoid contained in oysters and sea squirts, and TRAIL drastically induced apoptosis in colon cancer DLD-1 cells, whereas each agent alone only slightly induced apoptosis. The combination induced nuclear condensation and poly(ADP-ribose) polymerase cleavage, which are major features of apoptosis. Various caspase inhibitors could attenuate the apoptosis induced by this combination. Furthermore, the dominant-negative form of a TRAIL receptor could block the apoptosis, suggesting that halocynthiaxanthin specifically facilitated the TRAIL signaling pathway. To examine the molecular mechanism of the synergistic effect of the combined treatment, we did an RNase protection assay. Halocynthiaxanthin markedly up-regulated a TRAIL receptor, death receptor 5 (DR5), among the death receptor–related genes, suggesting a possible mechanism for the combined effects. Moreover, we examined whether other carotenoids also possess the same effects. Peridinin, but not alloxanthin, diadinochrome, and pyrrhoxanthin, induced DR5 expression and sensitized DLD-1 cells to TRAIL-induced apoptosis. These results indicate that the combination of certain carotenoids and TRAIL is a new strategy to overcome TRAIL resistance in cancer cells. (Mol Cancer Res 2007;5(6):615–25)