1. On a high-fat diet (HFD), mice genetically predisposed to colorectal cancer (ApcMin mice) developed fewer and smaller tumors when maintained on a diet-relevant low dose of resveratrol as compared to a much higher pharmacological dose.
2. Exposing cells from ApcMin mouse and human colorectal tumors to dietary rather than pharmacological doses of resveratrol resulted in increased adenosine monophosphate-activated protein kinase (AMPK) signaling, which may play a role in chemoprevention.
Evidence Rating Level: 2 (Good)
Study Rundown: Resveratrol is a phenol molecule found in the skins of grapes and berries. It has been widely studied for its beneficial effects on metabolism, heart disease, and cancer prevention, but the results of pilot studies have remained inconclusive. Here, the authors hypothesized that contradictory findings may stem from the inconsistency between dietary intake of low amounts of resveratrol in retrospective observational studies and higher, pharmacological doses used in experimental studies.
ApcMin mice were fed either a standard diet (SD) or HFD, the latter of which further promotes tumor development. Daily supplementation with low-dose resveratrol reduced the size and number of developed adenomas in HFD- but not SD-fed mice. A lesser effect on tumor reduction was shown with the pharmacological dose, which was 200-fold higher than the dietary dose. Further experiments showed that AMPK activity in HFD-fed mice was significantly upregulated in the low-dose group but not in the high-dose group. Downstream targets of AMPK, which relate to cell autophagy and senescence and may therefore be chemopreventive, were also upregulated in the low-dose group. In in vitro experiments, incubating cells derived from ApcMin mouse adenomas with dietary doses of resveratrol resulted in increased activation of AMPK and its downstream markers. Similar results were observed with tumor explants from human patients, further supporting the conclusion that lower doses might be optimally effective for cancer prevention.
This study importantly establishes that lower, diet-relevant doses of resveratrol may have greater chemopreventive effects than higher ones. The safety of resveratrol is well characterized, facilitating the application of this work to clinical studies.
In-Depth [human and animal studies]: Initial pharmacokinetic experiments in humans tested whether dietary doses of resveratrol could be delivered to target tissues. Healthy volunteers ingested a single dietary (5 mg) or pharmacological (1.005 g) dose of radiolabeled resveratrol. Accelerator mass spectrometry and high performance liquid chromatography confirmed that for both doses, resveratrol was detectable in blood plasma after 24 hours. Colorectal cancer patients given the same doses daily for a week prior to surgical cancer resection showed detectable resveratrol levels in excised colorectal mucosa and muscle tissue.
Next, ApcMin mice were used to test the chemopreventive potential of dietary resveratrol doses. Feeding animals an HFD containing 60% fat led to increased tumor development compared to feeding with an SD containing 16% fat. Compared to animals that did not receive resveratrol, HFD-fed mice given low-dose resveratrol (0.07 mg/kg/day) for 10 weeks showed 40% fewer adenomas and a 52% decrease in total tumor volume (p<0.001, n=31-35 per group). A pharmacological resveratrol dose (14 mg/kg/day) resulted in 33% and 25% reductions in adenoma number and total volume, respectively. Western blotting showed increased AMPK activity in intestinal mucosa of HFD-fed animals given the low dose (p<0.05, n=6 per group) but not the high dose. Similarly, levels of the cell senescence marker p21 were increased only in the low-dose group (p<0.05).
Incubating cells from ApcMin mouse adenomas with 0.001-10 µM resveratrol for 6 days resulted in maximum AMPK activation at 1 µM (p<0.01 vs. 0 µM control), which corresponded with high levels of senescence (p<0.0005 vs. control). When tumor explants from several colorectal cancer patients were incubated with resveratrol for 2 hours, higher AMPK activity was observed at lower doses (0.01-0.1 µM) than higher ones.
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