Resveratrol displays converse dose-related effects on 5-fluorouracil-evoked colon cancer cell apoptosis: the roles of caspase-6 and p53.
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 microM) increased 5-FU-triggered apoptosis and caspase-6 activation. Lower doses (25 or 50 microM) inhibited 5-FU-mediated apoptosis and caspase-6 activation only in p53+/+ cells. Moreover, G(1)-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 microM) interacted with 5-FU in a synergistic manner (mean CI < 0.9). At lower doses (25 or 50 microM), 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.
Chan
Jason Yongsheng
JY
National University Medical Institute, National University of Singapore, Singapore.
Phoo
Meng Seng
MS
Clement
Marie-Veronique
MV
Pervaiz
Shazib
S
Lee
Shao Chin
SC
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053178:Caspase 6 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D053178:Caspase 6; D000077185:Resveratrol; D005472:Fluorouracil