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Research Paper

Resveratrol displays converse dose-related effects on 5-fluorouracil-evoked colon cancer cell apoptosis: The roles of caspase-6 and p53

Jason Yongsheng Chan, Meng Seng Phoo, Marie-Veronique Clement, Shazib Pervaiz and Shao Chin Lee

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We have reported that resveratrol (RSV) evoked apoptosis through caspase-6 activation in HCT116 human colon cancer cells wild-type (p53+/+) or knockout (p53-/-) for p53. In this study, the role of caspase-6 activation in 5-fluorouracil (5-FU)-elicited apoptosis as well as the combination effects between RSV and 5-FU on their apoptosis induction was further investigated in the same colon cancer cell model. The combination effects were determined by calculation of combination indices (CI). We found that 5-FU triggered apoptosis and caspase-6 activation in the cancer cells, which were entirely abrogated by caspase-6 inhibitors. RSV (200 µM) increased 5-FU-triggered apoptosis and caspase-6 activation. Lower doses (25 or 50 µM) inhibited 5-FU-mediated apoptosis and caspase-6 activation only in p53+/+ cells. Moreover, G1-arrest of the p53+/+ cells was elicited by lower doses of RSV and 5-FU in combination, but not with either agent alone. RSV (200 µM) interacted with 5-FU in a synergistic manner (mean CI < 0.9). At lower doses (25 or 50 µM), it interacted with 5-FU in antagonistic (mean CI > 1.1) and additive manners (0.9 < mean CI <1.1) in p53+/+ and p53-/- cells respectively. In conclusion, our results suggest that, like RSV, 5-FU triggers the cancer cell apoptosis by activating caspase-6. Their combination effect in apoptosis induction is dependent on the concentration of RSV and is mediated by caspase-6 activation. RSV synergistically promotes 5-FU-mediated apoptosis at its higher concentration irrespective of p53. Conversely, it inhibits 5-FU-triggered apoptosis at lower concentrations in p53+/+ cells.

Authors

Jason Yongsheng Chan

1National University Medical Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Meng Seng Phoo

1National University Medical Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Marie-Veronique Clement

3Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 4NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore

Shazib Pervaiz

2Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Shao Chin Lee

National University Medical Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

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If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.