Resveratrol is gaining attention for its anticancer effects and is also recognized for its antioxidant properties and influence on glucose metabolism. Augmented reactive oxygen species (ROS) and high glycolytic flux are common characteristics of malignant cells. We thus evaluated the effect of resveratrol on cancer cell glucose metabolism and investigated the role of ROS in the response. Methods: Cancer cells were measured for cell content and 18 F-FDG uptake. Assays were performed for lactate production; hexokinase activity and intracellular ROS; and immunoblotting for hypoxia-inducible factor-1a (HIF-1a), Akt, mammalian target of rapamycin, and glucose transporter type 1 (Glut-1). Animal studies were performed with small-animal PET imaging of Lewis lung carcinoma tumor-bearing mice. Results: Resveratrol mildly decreased cell content and more pronouncedly suppressed 18 F-FDG uptake in Lewis lung carcinoma, HT-29 colon, and T47D breast cancer cells. Hence, 18 F-FDG uptake normalized to cell content was reduced to less than half of controls by 24-h exposure to resveratrol. This reduction was attributed to reduced glycolytic flux and Glut-1 expression. Resveratrol also decreased intracellular ROS in patterns that closely paralleled 18 F-FDG uptake. Scavenging of ROS with N-acetyl cysteine, but not inhibition of nicotinamide adenine dinucleotide phosphate oxidase, was sufficient to suppress 18 F-FDG uptake. Conversely, ROS inducers effectively reversed the metabolic response of resveratrol. HIF-1a protein was markedly reduced by resveratrol, and inhibiting HIF-1a expression with cycloheximide or specific small interfering RNAs suppressed 18 F-FDG uptake. The proteosomal inhibitor MG132 partly restored HIF-1a level and 18 F-FDG uptake in resveratrol-treated cells. Resveratrol also inhibited Akt activation; in addition, inhibitors and small interfering RNAs against phosphoinositide 3-kinase decreased 18 F-FDG uptake. Finally, small-animal PET results showed resveratrol treatment to suppress tumor 18 F-FDG uptake in vivo. Conclusion: Resveratrol suppresses cancer cell 18 F-FDG uptake and glycolytic metabolism in a manner that depends on the capacity of resveratrol to inhibit intracellular ROS, which downregulates HIF-1a accumulation. Ther e is recently growing interest in natural products as an addition to the repertoire of agents that may be beneficial in our battle against cancer (1). Resveratrol, a natural polyphenol compound found in such fruits as grapes and berries, has particularly gained intense attention for its promising anticancer effects (2). Initially recognized for its ability to inhibit carcinogenesis at multiple stages (3,4), resveratrol has since been found to exert significant antitumor effects including inhibition of growth (5-7), induction of apoptosis (6-8), and suppression of metastatic potential (9,10).Resveratrol is known to reduce energy expenditure in vivo, mimicking the effects of caloric restriction (11). Recently, several in vitro studies have described an inhibitory effect of resveratrol ...

For 18 F-FDG PET to be widely used to monitor atherosclerosis progression and therapeutic response, it is crucial to better understand how macrophage glucose metabolism is influenced by the atherosclerotic microenvironment and to elucidate the molecular mechanisms of this response. Oxidized low-density lipoprotein (oxLDL) is a key player in atherosclerotic inflammation that promotes macrophage recruitment, activation, and foam cell formation. We thus explored the effect of oxLDL on macrophage 18 F-FDG uptake and investigated the underlying molecular mechanism including the roles of hypoxia-inducible factor-1α (HIF-1α) and reactive oxygen species (ROS). Methods: RAW264.7 macrophages were stimulated with native LDL, oxLDL, or lipopolysaccharide. Cells were assessed for 18 F-FDG uptake, lactate production, membrane glucose transporter 1 (GLUT1) expression, and hexokinase activity. ROS generation, Nox expression, and HIF-1α activity were also measured. Results: oxLDL (20 μg/mL) induced a 17.5 ± 1.7-fold increase in macrophage 18 F-FDG uptake by 24 h, which was accompanied by increased lactate production, membrane GLUT1 expression, and hexokinase activity. oxLDL-stimulated 18 F-FDG uptake was completely blocked by inhibitors of Src or phosphoinositide 3-kinase. ROS generation was increased to 262.4% ± 17.9% of controls by oxLDL, and N-acetyl-L-cysteine completely abrogated both oxLDLinduced ROS production and 18 F-FDG uptake. oxLDL increased Nox2 expression, and nicotinamide adenine dinucleotide phosphate oxidase inhibition totally blocked increased ROS generation and 18 F-FDG uptake by oxLDL. Finally, there was a clear ROSdependent increase of HIF-1α accumulation by oxLDL, and silencing of HIF-1α completely abolished the metabolic effect of oxLDL. Conclusion: oxLDL is a strong stimulator of macrophage 18 F-FDG uptake and glycolysis through upregulation of GLUT1 and hexokinase. This metabolic response is mediated by Nox2-dependent ROS generation that promotes HIF-1α activation.

No abstract