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Title: Lower concentrations of blueberry polyphenolic-rich extract differentially alter HepG2 cell proliferation and expression of genes related to cell-cycle, oxidation and epigenetic machinery

item Shafiee-Morrel, Farideh
item Grusak, Michael
item Gustafson, Sally
item LILA, MARY - North Carolina State University
item NICULESCU, MIHAI - University Of North Carolina

Submitted to: Journal of Nutritional Disorders & Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/12/2012
Publication Date: 11/22/2012
Citation: Shafiee-Morrel, F., Grusak, M.A., Gustafson, S.J., Lila, M.A., Niculescu, M.D. 2012. Lower concentrations of blueberry polyphenolic-rich extract differentially alter HepG2 cell proliferation and expression of genes related to cell-cycle, oxidation and epigenetic machinery. Journal of Nutritional Disorders & Therapy. 3:120.

Interpretive Summary: Blueberries contain compounds that are believed to promote good health in humans. One area of interest is in the so-called anti-oxidant compounds, found in blueberries and other plant foods, which might play a role in the prevention or progression of certain cancers. In this study, we grew cancer cells from a human liver cancer, using a technique in which cells are grown in a single layer on sterile plates. We treated these cells with various concentrations of a blueberry extract and then measured the growth of the cancer cells over time, along with any changes in the cancer cell's metabolism. We identified certain low doses of blueberry extracts that reduced the growth of the cancer cells, relative to the other extract concentrations tested. We also gained a better understanding of some of the cellular changes that impacted cancer cell growth.

Technical Abstract: In vitro cancer models have been used to study the effect of relatively high concentrations (>200 ug/ml) of phenolic plant extracts upon cell proliferation. In this study we report that the treatment of human hepatocarcinoma HepG2 cells with lower concentrations of blueberry phenolic extract (6.5-100 ug/mL) for 96 h induced a non-linear response in cell proliferation, with a significant peak at 25 ug/mL and lower proliferation observed at higher concentrations, while no differences in apoptosis were present across groups. Flow cytometry analysis indicated a reduction of almost 19% of cells in S-phase for 25 ug/mL, as compared to control, whereas no changes were observed for other concentrations. The percent of cells in G2/M phase was reduced at 50 ug/ml, while all other concentrations increased the percent of cells in G0/G1 phase. Gene expression analysis revealed concentration-specific changes for several genes involved in cell-cycle regulation (cyclin D1, cyclin-dependent kinase inhibitor 1A, and proliferating cell nuclear antigen, PCNA), antioxidant metabolism (glutamate-cysteine ligase catalytic subunit and glutathione reductase), and epigenetic machinery related to cell-cycle progression (DNA-methyltransferase 1, DNA-methyltransferase 3a, and Sirtuin 1). Neither the generation of reactive oxygen species (ROS) nor the intracellular redox status was affected by any treatment. Taken together, these data indicate that lower concentrations of blueberry phenolic extracts induce differential effects upon cell proliferation and the expression of genes involved in cell-cycle progression and epigenetic machinery in HepG2 cells. These findings provide insight into the molecular mechanisms associated with concentration-specific alterations induced by blueberry polyphenols upon cell growth and proliferation in these cells.