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 G2 -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.

中文翻译：

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姜黄素与3',4'-二去甲基川胆碱联合对结肠癌细胞的协同抗癌作用

结合使用多种膳食生物活性成分及其代谢物的化学预防策略因其低毒性和潜在的协同相互作用而具有优势。在此，我们首次研究了姜黄素和川陈皮素的主要代谢物 3',4'-二去甲基川金香素 (DDMN) 的组合，以确定它们在抑制人结肠癌细胞生长方面的组合作用。等效线图分析揭示了姜黄素和 DDMN 在抑制 HCT116 结肠癌细胞生长方面的协同相互作用。联合治疗诱导了显着的 G2-M 细胞周期停滞和广泛的细胞凋亡，这大大超过了姜黄素或 DDMN 单独治疗的效果。与这些增强的抗癌作用相关的蛋白质是 p53、p21、HO-1、c-聚（ADP-核糖）聚合酶、Cdc2 和 Cdc25c；每种蛋白质都被证实受到联合治疗的显着影响，而不是单独的单独治疗。有趣的是，在细胞培养基中存在 DDMN 时也观察到姜黄素的稳定性增加，这可以部分解释姜黄素和 DDMN 之间的协同相互作用。应该进一步探索姜黄素和 DDMN 之间这种新发现的协同作用，以确定其在体内对结肠癌的化学预防潜力。实际应用：本研究首次确定了姜黄中存在的膳食成分姜黄素与川芎素（一种独特的柑橘类黄酮）的代谢物相结合对结肠癌细胞生长的协同抑制作用。该组合的协同作用可能是由于该组合诱导的细胞周期停滞和细胞凋亡，以及由于川陈皮苷代谢物的抗氧化特性而导致姜黄素稳定性的改善。姜黄素和川陈皮素代谢物之间协同作用的这些重要发现可以提供潜在的抗结肠癌化学预防价值。