Abstract
We have used a perfusion bellows cell culture system to investigate resveratrolinduced anti-proliferation/apoptosis in a human estrogen receptor (ER)-negative breast cancer cell line (MDA-MB-231). Using an injection system to perfuse media with stilbene, we showed resveratrol (0.5 - 100 μM) to decrease cell proliferation in a concentration-dependent manner. Comparison of influx and medium efflux resveratrol concentrations revealed rapid disappearance of the stilbene, consistent with cell uptake and metabolism of the agent reported by others. Exposure of cells to 10 μM resveratrol for 4 h daily × 6 d inhibited cell proliferation by more than 60%. Variable extracellular acid-alkaline conditions (pH 6.8 - 8.6) affected basal cell proliferation rate, but did not alter anti-proliferation induced by resveratrol. Resveratrol-induced gene expression, including transcription of the most up-regulated genes and pro-apoptotic p53-dependent genes, was not affected by culture pH changes. The microarray findings in the context of induction of anti-proliferation with brief daily exposure of cells to resveratrol-and rapid disappearance of the compound in the perfusion system-are consistent with existence of an accessible initiation site for resveratrol actions on tumor cells, e.g., the cell surface receptor for resveratrol described on integrin αvβ3.
Highlights
Resveratrol is a naturally occurring polyphenol whose complex cellular actions are cell cycle arrest, differentiation, and apoptosis [1].These cellular actions may reflect a reduction in intracellular reactive oxygen species (ROS) and mitochondrial trans-membrane potential Δ ψm, as well as reduced phosphorylation of mTOR, RP-S6 and 4EBP1 [2]
This study investigated effects of resveratrolinduced anti-proliferation in triple-negative MDAMB-231 breast cancer cells, but the results shown may be applicable to other cancer cells
When low concentrations of resveratrol were used in the current studies, the efflux concentrations of resveratrol were far below the projected concentrations (Fig. 4C); this is consistent with the short biological half-life of the agent described by others [27]
Summary
Resveratrol (trans-3, 4′, 5-trihydroxystilbene) is a naturally occurring polyphenol whose complex cellular actions are cell cycle arrest, differentiation, and apoptosis [1]. These cellular actions may reflect a reduction in intracellular reactive oxygen species (ROS) and mitochondrial trans-membrane potential Δ ψm, as well as reduced phosphorylation of mTOR, RP-S6 and 4EBP1 [2]. A cell surface receptor for the stilbene has been identified on integrin αvβ and has been shown to be linked to activation of the MAPK signal transduction pathway [6]. The Arg-Gly-Asp (RGD) recognition site on the integrin blocks actions of the stilbene, indicating proximity of the resveratrol receptor to the RGD site [6, 7]. The mechanisms of anti-tumor effects of resveratrol are incompletely understood, but an end result in a variety of tumor cell models of resveratrol treatment is apoptosis [8,9,10]
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