Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines

Abstract

Purpose: We examined the effects of the phytochemical resveratrol in six human cancer cell lines (MCF7, SW480, HCE7, Seg-1, Bic-1, and HL60).

Experimental design and results: Resveratrol induced marked growth inhibition in five of these cell lines, with IC(50) values of approximately 70-150 microM. However, only partial growth inhibition was seen in Bic-1 cells. After treatment with 300 microM resveratrol for 24 h, most of the cell lines were arrested in the S phase of the cell cycle. In addition, induction of apoptosis was demonstrated by the appearance of a sub-G(1) peak and confirmed using an annexin V-based assay. Cyclin B1 expression levels were decreased in all cell lines after 48 h of treatment. In SW480 cells, cyclin A, cyclin B1, and beta-catenin expression levels were decreased within 24 h. There was a decrease in cyclin D1 expression after only 2 h of treatment, and this persisted for up to 48 h. This decrease was partially blocked by concurrent treatment with the proteasome inhibitor calpain inhibitor I. Using a luciferase-based reporter assay, resveratrol did not inhibit cyclin D1 promoter activity in SW480 cells. Furthermore, using a reverse transcription-PCR-based assay, only a higher dose of resveratrol (300 microM) appeared to decrease cyclin D1 mRNA. Seg-1 cells expressed basal levels of cyclooxygenase-2 (cox-2), which was further induced by resveratrol. Neither basal levels nor induction of cox-2 was detectable in the remaining cell lines. Thus, cox-2 does not appear to be a critical target of this compound.

Conclusions: These studies provide support for the use of resveratrol in chemoprevention and cancer therapy trials. Cyclin D1, cyclin B1, beta-catenin, and apoptotic index could be useful biomarkers to evaluate treatment efficacy.