Clinical Pharmacology of Resveratrol and Its Metabolites in Colorectal Cancer Patients

Abstract

Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4′-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4′-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.

Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

“…However, various lines of evidence indicate that in vitro doses that have been shown to induce apoptotic cell death could be achieved in cancer cells through higher intake of resveratrol (87)(88)(89)(90)(91). For example, resveratrol at daily doses of up to 5 g for 29 days is not toxic to humans, and daily doses of 0.5 or 1 g produce levels of resveratrol in tumor cells that are sufficient to elicit anticancer effects such as induction of apoptosis in cancer cells (88). Additionally, further research on resveratrol modifications may increase the bioavailability of resveratrol in cancer tissues.…”

Resveratrol Administration Increases Transthyretin Protein Levels, Ameliorating AD Features: The Importance of Transthyretin Tetrameric Stability

“…Alternatively, the mix underwent denaturation by urea and the generated species were crosslinked with glutaraldehyde, after which the samples were analyzed by a standard SDS-PAGE ( Figure 5A2), to evaluate the levels of folded TTR (tetramer, trimer 1% when administered orally) (39), and therefore studies have been performed using high doses (50-300 mg/kg/day) (40) in mice. The corresponding human dose, using a scaling factor of 0.08, is approximately 1 g. This concentration was found to be within the range of doses used in human studies, in which 1 g of resveratrol was shown to be well tolerated (41).…”

Plant-derived anticancer agents: a promising treatment for bone metastasis

“…In cancer, a phase I clinical trial to study the pharmacology of resveratrol and its metabolites in patients with colorectal cancer was completed recently. 61 Twenty patients were treated with resveratrol at a dose of 0.5 or 1.0 g before surgical resection. Resveratrol was well tolerated, and daily doses of 0.5 or 1.0 g were recommended to obtain anticarcinogenic effects.…”

“…Resveratrol was well tolerated, and daily doses of 0.5 or 1.0 g were recommended to obtain anticarcinogenic effects. 61 Despite these interesting results, there are currently no clinical trials testing the effect of resveratrol on bone metastases.…”