Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue

Abstract

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. Cancer Prev Res; 3(8); 929-39. ©2010 AACR.

The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis

“…Its mutant or stability greatly determines the sensitivity of tumor cells to quercetin. As described in the literature, the GI50 was about 12-24μM in the p53 wild type tumor cells [23,24], but was more than 190μM in the p53 mutant cell [25]. The phenomenon was also demonstrated in our study, although the numerical value was different, the trend was same.…”

Inhibition of prostate cancer cell growth by 3′,4′,5′-trimethoxyflavonol (TMFol)

“…In contrast, TRAMP C2 tumours in mice which received fisetin or quercetin with their diet at an isomolar dose grew at the same rate as those in animals on control diet (Supplemental Fig 1). As observed previously in the Apc Min mouse model [7], the body weight of the mice which received TMFol was indistinguishable from that of mice on control diet, consistent with the notion that the intervention does not adversely affect the mice.…”

“…TMFol possessed colorectal cancer chemopreventive efficacy in the Apc Min mouse model, which was superior to that of quercetin or fisetin [7]. Furthermore, TMFol lacked the mutagenic properties of its flavonol congeners.…”

Hesperidin Induces Apoptosis by Inhibiting Sp1 and Its Regulatory Protein in MSTO-211H Cells

“…Representative flavonoids like resveratrol, quercetin, curcumin and EGCG are studied for clinical trials (Shanafelt et al , 2009; Howells et al , 2010; la Porte et al , 2010; Kanai et al , 2011). However, it has not yet been developed for clinical treatments regarding cancer therapy.…”