Department of Cancer Studies and Molecular Medicine, University of Leicester, United Kingdom.
Cancer Prev Res (Phila). 2010 Aug;3(8):929-39. doi: 10.1158/1940-6207.CAPR-09-0236. Epub 2010 Jul 13.
Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3',4',5'-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, Apc(Min) mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of Apc(Min) or from either day 7 before ("TMFol early") or day 7 after ("TMFol late") tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in Apc(Min) mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in Apc(Min) and 1.5-fold in HCT116 tumor-bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents.
一些天然存在的类黄酮醇，如槲皮素，似乎具有实验性的癌症化学预防功效。p53 的调节被认为是其活性的一种机制。研究假设一种合成的类黄酮醇，3'，4'，5'-三甲氧基黄酮醇（TMFol），可以在两种结直肠癌发生模型中干扰肿瘤的发展和 p53 的表达，即 Apc(Min)小鼠和人源 HCT116 结肠癌裸鼠。从断奶到 Apc(Min)小鼠的第 16 周，或从 HCT116 小鼠肿瘤接种前 7 天（“TMFol 早期”）或接种后 7 天（“TMFol 晚期”）开始，用 TMFol 饮食（0.2%）喂养小鼠。通过 Ki-67 或 cleaved caspase-3 染色分别研究 TMFol 对 HCT116 肿瘤中肿瘤增殖或凋亡的影响。通过高效液相色谱法测量 TMFol 肿瘤水平。与对照组相比，TMFol 可使 Apc(Min)小鼠的小肠腺瘤负担减少 47%（P < 0.002）。TMFol 早期方案使 HCT116 肿瘤大小减少近一半（P < 0.05），降低肿瘤增殖，增加凋亡，而与对照组相比，TMFol 晚期方案无显著影响。在 TMFol 减少肿瘤发展的小鼠肿瘤组织中，Apc(Min)和 HCT116 荷瘤小鼠的 p53 表达分别增加 3 倍和 1.5 倍（P = 0.02）。TMFol 还增加了源自这些肿瘤的细胞中的 p53。在 HCT116 肿瘤中检测到 TMFol，但水平与肿瘤负担无关。TMFol 在 Ames 试验中没有致突变性。结果表明，类黄酮醇结构的化学修饰可能产生安全有效的癌症化学预防剂。
