Department of Clinical Oncology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
Cancer Sci. 2011 May;102(5):1045-51. doi: 10.1111/j.1349-7006.2011.01886.x. Epub 2011 Feb 24.
Curcumin is a dietary constituent with tumor-suppressing potential, inhibiting various pathways involved in carcinogenesis. However, because of its low bioavailability, the use of curcumin in in vivo trials has been limited. To overcome this problem, we synthesized more than 50 analogs and identified a monoketone analog, GO-Y030, which has a 30-fold higher potential to suppress tumor cell growth compared with curcumin. We investigated the inhibitory effect of GO-Y030 on NF-κB activation. In thyroid, pancreatic cancers and cholangiocarcinoma cells, in which NF-κB is activated, NF-κB activation was suppressed to 8-62% of the control value following treatment with 1 μM GO-Y030, an effect comparable to that of 10 μM curcumin. Direct inhibition of IKKβ kinase activity and suppression of nuclear translocation of the NF-κB p65 subunit were observed. The 50% growth inhibition concentrations of GO-Y030 ranged from one-11th to one-14th of those of curcumin. GO-Y030 also induced cell death comparable to that induced by curcumin but at a 10-fold lower concentration. In pancreatic and thyroid cancer cells, the growth-inhibitory effect of GO-Y030 was 4- and 15-fold greater, respectively, than that of curcumin. GO-Y030 was a much stronger inducer of apoptosis compared with curcumin. The enhanced potency of GO-Y030 may make it more useful than curcumin, which suffers from low bioavailability. GO-Y030 is a good lead compound for the development of useful compounds for practical cancer chemotherapy.
姜黄素是一种具有肿瘤抑制潜力的膳食成分，可抑制致癌作用涉及的多种途径。然而，由于其生物利用度低，姜黄素在体内试验中的应用受到限制。为了克服这个问题，我们合成了 50 多个类似物，并确定了一种单酮类似物 GO-Y030，其抑制肿瘤细胞生长的潜力比姜黄素高 30 倍。我们研究了 GO-Y030 对 NF-κB 激活的抑制作用。在甲状腺癌、胰腺癌和胆管细胞癌中，NF-κB 被激活，用 1μM GO-Y030 处理后，NF-κB 的激活被抑制到对照值的 8-62%，这一效果与 10μM 姜黄素相当。观察到 IKKβ激酶活性的直接抑制和 NF-κB p65 亚单位的核易位受到抑制。GO-Y030 的 50%生长抑制浓度范围为姜黄素的 1/11 至 1/14。GO-Y030 还诱导了与姜黄素相当的细胞死亡，但浓度低 10 倍。在胰腺癌和甲状腺癌细胞中，GO-Y030 的生长抑制作用分别比姜黄素高 4 倍和 15 倍。GO-Y030 比姜黄素更能诱导细胞凋亡。与姜黄素相比，GO-Y030 的效力更强。GO-Y030 可能比生物利用度低的姜黄素更有用，是开发用于实用癌症化疗的有用化合物的良好先导化合物。
