The anthocyanin metabolites gallic acid, 3-O-methylgallic acid, and 2,4,6-trihydroxybenzaldehyde decrease human colon cancer cell viability by regulating pro-oncogenic signals
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Sarah C Forester1, Ying Y Choy, Andrew L Waterhouse
1Department of Viticulture and Enology, One Shields Avenue, University of California, Davis.
Abstract:
Anthocyanins are a class of polyphenols abundant in the skins of red grapes, and have been shown to have anti-cancer effects in models of colon cancer [Cooke et al. Int J Cancer 2006;119:2213-2220; Jing et al. J Agric Food Chem 2008;56:9391-9398]. Gut microflora metabolize anthocyanins to phenolic acids and aldehydes. These metabolites may explain the relationship between anthocyanin consumption and reduced incidence of colorectal cancer (CRC). Previously, gallic acid (Gal), 3-O-methylgallic acid (Megal), and 2,4,6-trihydroxybenzaldehyde (THBA) were found to decrease Caco-2 cell viability to a larger extent than other anthocyanin metabolites. To better understand the potential anti-CRC action of these compounds, this paper investigated their capacity to modulate the cell cycle, and induce apoptotic cell death. Dividing Caco-2 cells were incubated for 24-72 h in the presence of 10-100 µM Gal, Megal, THBA, and malvidin-3-glucoside (M3g). THBA reduced cell viability only at 100 µM, while Gal and Megal (10-100 µM) caused a time- and dose-dependent decrease in cell viability. After 72 h incubation, the metabolites caused cell cycle arrest at G0 /G1 . The activation of the apoptotic pathway by Megal, Gal, and THBA was evidenced by the activation of caspase-3. However, only Megal and Gal caused DNA fragmentation and nuclear condensation. Megal, Gal, and THBA inhibited transcription factors NF-κB, AP-1, STAT-1, and OCT-1 which are known to be activated in CRC. In conclusion, the anti-cancer effects of Megal and Gal occurs as a consequence of both the inhibition of cell proliferation and induction of apoptosis. The inhibition of transcription factors that promote cell proliferation and survival can in part underlie the observed effects.
Insights
Anthocyanin metabolites, gallic acid (Gal) and 3-O-methylgallic acid (Megal), inhibit colon cancer cell proliferation and induce apoptosis. These compounds also block key transcription factors involved in colorectal cancer (CRC) progression.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Anthocyanins, found in red grape skins, exhibit anti-cancer properties against colon cancer models.
- Gut microflora metabolize anthocyanins into phenolic acids and aldehydes, which may mediate their anti-cancer effects.
- Gallic acid (Gal), 3-O-methylgallic acid (Megal), and 2,4,6-trihydroxybenzaldehyde (THBA) were previously identified as potent Caco-2 cell viability reducers.
Purpose of the Study:
- To investigate the capacity of anthocyanin metabolites (Gal, Megal, THBA) to modulate cell cycle and induce apoptosis in colon cancer cells.
- To elucidate the mechanisms underlying the potential anti-colorectal cancer (CRC) action of these metabolites.
Main Methods:
- Caco-2 cells were incubated with varying concentrations (10-100 µM) of Gal, Megal, THBA, and malvidin-3-glucoside (M3g) for 24-72 hours.
- Cell viability, cell cycle progression (G0/G1 arrest), apoptosis (caspase-3 activation, DNA fragmentation, nuclear condensation), and transcription factor activity (NF-κB, AP-1, STAT-1, OCT-1) were assessed.
Main Results:
- Gal and Megal significantly decreased Caco-2 cell viability in a time- and dose-dependent manner.
- All tested metabolites induced cell cycle arrest at the G0/G1 phase after 72 hours.
- Megal, Gal, and THBA activated caspase-3, indicating apoptosis induction; Megal and Gal additionally caused DNA fragmentation and nuclear condensation.
- Megal, Gal, and THBA inhibited transcription factors NF-κB, AP-1, STAT-1, and OCT-1, which are implicated in CRC.
Conclusions:
- The anti-cancer effects of Megal and Gal against colon cancer cells stem from the inhibition of cell proliferation and induction of apoptosis.
- Inhibition of transcription factors crucial for cell proliferation and survival pathways contributes to the observed anti-cancer effects of these anthocyanin metabolites.
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