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In addition to its bactericidal properties, there is multiple evidence that resveratrol is able to inhibit cell proliferation of human adenocarcinoma cell lines, but the mechanisms underlying its action remain unknown. Since resveratrol has been shown to mediate apoptosis through a variety of different pathways, resveratrol-induced apoptosis seems to be one of the inhibitory mechanisms in GC. Several authors have shown that the resveratrol-induced apoptotic program is consequent to its inhibition of cell proliferation.
Atten et al found that exposure of KATO-III and RF-1 cells and SNU-1 cells to resveratrol (100 μmol/L for 24 h) interfered with cell cycle progression, inhibited DNA synthesis and suppressed cellular proliferation. Moreover, resveratrol suppressed nitrosamines-stimulated DNA synthesis in RF-1 cells, showing that, in addition to suppressing normal cellular proliferation, resveratrol was able to reverse carcinogen-stimulated proliferation. Resveratrol induced inhibition of protein kinase C (PKC) activity in KATO-III cells, without any change in mitogen-activated protein kinases ERK1/ERK2 activity, suggesting that resveratrol utilizes a PKC-mediated mechanism to inhibit growth of gastric adenocarcinoma cells.
This finding is significant when considering that inhibitors of PKC have been studied as potential anticancer agents precisely because they are associated with tumor suppression, cell cycle arrest, decreased proliferation, and apoptosis. Gastric adenocarcinoma SNU-1 cells treated with resveratrol showed a time- and concentration-dependent increase in tumor suppressors p21(cip1/WAF-1) and p53 preceded by the loss of membrane-associated PKC δ protein and by a concomitant increase in cytosolic PKC α Resveratrol also caused a time-dependent accumulation of Fas and Fas-L proteins in SNU-1 cells while it had no effect on Fas but did elevate Fas-L in p53 deficient KATO-III cells.
Riles et al found that individual gastric carcinoma cell lines respond to resveratrol (100 μmol/L) with engagement of individual apoptotic signals. They investigated the role of p53 in the intracellular apoptotic signals engaged by resveratrol. Resveratrol induced a time-dependent apoptotic response in the three cell lines analyzed irrespective of their p53 status. In p53 expressing SNU-1 cells resveratrol up-regulated p53 and down-regulated surviving, whereas in KATO-III cells (not expressing p53) and in AGS cells, resveratrol stimulated caspase 3 and cytochrome C oxidase activities, enabling suppression of proliferation while stimulating the breakdown of nuclear proteins.
Treatment with resveratrol (50-200 μmol/L) for 48 h significantly induced apoptosis and DNA damage in human GC SGC-7901 cells. These effects were due to the increased generation of ROS following resveratrol treatment, corroborated by the fact that incubation of cells with superoxide dismutase or catalase attenuated resveratrol-induced cellular apoptosis. Exposure to resveratrol (100 μmol/L) for 24 h induced cell death and cell cycle arrest in SNU-1 GC cells and the combination of resveratrol and dimethylsphingosine increased cytotoxicity, demonstrating that sphingolipid metabolites intensify resveratrol activity.
Article Produced By
Aida Zulueta, Anna Caretti, Paola Signorelli, Riccardo Ghidoni, Department of Health Sciences, San Paolo Hospital, University of Milan, 20142 Milano, Italy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588085/
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