Dept. of Food Science, Univ. of Massachusetts, Amherst, MA, 01003, USA.
Inst. of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
J Food Sci. 2020 Apr;85(4):1292-1301. doi: 10.1111/1750-3841.15073. Epub 2020 Mar 6.
Chemoprevention strategies employing the use of multiple dietary bioactive components and their metabolites in combination offer advantages due to their low toxicity and potential synergistic interactions. Herein, for the first time, we studied the combination of curcumin and 3',4'-didemethylnobiletin (DDMN), a primary metabolite of nobiletin, to determine their combinatory effects in inhibiting growth of human colon cancer cells. Isobologram analysis revealed a synergistic interaction between curcumin and DDMN in the inhibition of cell growth of HCT116 colon cancer cells. The combination treatment induced significant G -M cell-cycle arrest and extensive apoptosis, which greatly exceeded the effects of individual treatments with curcumin or DDMN. Proteins associated with these heightened anticarcinogenic effects were p53, p21, HO-1, c-poly(ADP-ribose) polymerase, Cdc2, and Cdc25c; each of the proteins was confirmed to be substantially impacted by the combination treatment, more than by individual treatments alone. Interestingly, an increase in the stability of curcumin was also observed with the presence of DDMN in cell culture medium, which could offer an explanation in part for the synergistic interaction between curcumin and DDMN. This newly identified synergy between curcumin and DDMN should be explored further to determine its chemopreventive potential against colon cancer in vivo. PRACTICAL APPLICATION: This study identifies for the first time the synergistic inhibition of colon cancer cell growth by the dietary component curcumin present in turmeric, in combination with a metabolite of nobiletin, a unique citrus flavonoid. The synergism of the combination may be due to cell-cycle arrest and apoptosis induced by the combination as well as an improvement in the stability of curcumin as a result of the antioxidant property of the nobiletin metabolite. These significant findings of synergism between curcumin and the nobiletin metabolite could offer potential chemopreventive value against colon cancer.
化学预防策略采用多种膳食生物活性成分及其代谢物的联合应用具有优势，因为它们的毒性低，并且具有潜在的协同作用。在此，我们首次研究了姜黄素与川陈皮素（一种川陈皮素的主要代谢物）的联合应用，以确定它们在抑制人结肠癌细胞生长方面的组合效应。棋盘分析显示，姜黄素和 DDMN 联合抑制 HCT116 结肠癌细胞生长具有协同作用。联合治疗诱导了显著的 G2-M 细胞周期阻滞和广泛的细胞凋亡，这大大超过了姜黄素或 DDMN 单独处理的效果。与这些增强的抗癌作用相关的蛋白质是 p53、p21、HO-1、c-poly（ADP-核糖）聚合酶、Cdc2 和 Cdc25c；证实每种蛋白质都受到联合治疗的显著影响，而不仅仅是单独治疗的影响。有趣的是，在细胞培养物中存在 DDMN 时，还观察到姜黄素的稳定性增加，这部分解释了姜黄素和 DDMN 之间的协同作用。应该进一步研究姜黄素和 DDMN 之间新发现的协同作用，以确定其在体内预防结肠癌的化学预防潜力。 实际应用：本研究首次确定了姜黄素（存在于姜黄中的膳食成分）与川陈皮素的代谢物联合抑制结肠癌细胞生长的协同作用，川陈皮素是一种独特的柑橘类黄酮。这种组合的协同作用可能是由于组合诱导的细胞周期停滞和细胞凋亡以及由于桔皮素代谢物的抗氧化特性导致姜黄素稳定性的提高。姜黄素和桔皮素代谢物之间协同作用的这些显著发现可能为结肠癌的化学预防提供潜在的价值。
