Tamvakopoulos Constantin, Dimas Konstantinos, Sofianos Zacharias D, Hatziantoniou Sophia, Han Zhiyong, Liu Zhong-Li, Wyche James H, Pantazis Panayotis
Division of Pharmacology-Pharmacotechnology, Foundation for Biomedical Research, Academy of Athens, Greece.
Clin Cancer Res. 2007 Feb 15;13(4):1269-77. doi: 10.1158/1078-0432.CCR-06-1839.
The plant-derived compound curcumin has shown promising abilities as a cancer chemoprevention and chemotherapy agent in vitro and in vivo but exhibits poor bioavailability. Therefore, there is a need to investigate modified curcumin congeners for improved anticancer activity and pharmacokinetic properties.
The synthetic curcumin analogue dimethoxycurcumin was compared with curcumin for ability to inhibit proliferation and apoptosis of human HCT116 colon cancer cells in vitro by estimating the GI(50) and LC(50) values and detecting the extent of apoptosis by flow cytometry analysis of the cell cycle. Metabolic stability and/or identification of metabolites were evaluated by recently developed mass spectrometric approaches after incubation with mouse and human liver microsomes and cancer cells in vitro. Additionally, circulating levels of dimethoxycurcumin and curcumin were determined in mice following i.p. administration.
Dimethoxycurcumin is significantly more potent than curcumin in inhibiting proliferation and inducing apoptosis in HCT116 cells treated for 48 h. Nearly 100% of curcumin but <30% of dimethoxycurcumin was degraded in cells treated for 48 h, and incubation with liver microsomes confirmed the limited metabolism of dimethoxycurcumin. Both compounds were rapidly degraded in vivo but dimethoxycurcumin was more stable.
Compared with curcumin, dimethoxycurcumin is (a) more stable in cultured cells, (b) more potent in the ability to kill cancer cells by apoptosis, (c) less extensively metabolized in microsomal systems, and (d) more stable in vivo. It is likely that the differential extent of apoptosis induced by curcumin and dimethoxycurcumin in vitro is associated with the metabolite profiling and/or the extent of stability.
植物源化合物姜黄素在体外和体内均显示出作为癌症化学预防和化疗药物的潜力，但生物利用度较差。因此，有必要研究修饰的姜黄素类似物，以提高其抗癌活性和药代动力学性质。
通过估计GI(50)和LC(50)值，并通过细胞周期的流式细胞术分析检测凋亡程度，比较合成姜黄素类似物二甲氧基姜黄素与姜黄素在体外抑制人HCT116结肠癌细胞增殖和凋亡的能力。在与小鼠和人肝微粒体及癌细胞体外孵育后，采用最近开发的质谱方法评估代谢稳定性和/或代谢物鉴定。此外，腹腔注射后测定小鼠体内二甲氧基姜黄素和姜黄素的循环水平。
在处理48小时的HCT116细胞中，二甲氧基姜黄素在抑制增殖和诱导凋亡方面比姜黄素显著更有效。在处理48小时的细胞中，近100%的姜黄素被降解，但二甲氧基姜黄素的降解率<30%，与肝微粒体孵育证实二甲氧基姜黄素代谢有限。两种化合物在体内均迅速降解，但二甲氧基姜黄素更稳定。
与姜黄素相比，二甲氧基姜黄素(a)在培养细胞中更稳定，(b)通过凋亡杀死癌细胞的能力更强，(c)在微粒体系统中代谢程度更低，(d)在体内更稳定。姜黄素和二甲氧基姜黄素在体外诱导凋亡的差异程度可能与代谢物谱和/或稳定性程度有关。
