Resveratrol induces colon tumor cell apoptosis independently of p53 and preceded by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

Resveratrol, a polyphenol present in wine and grapes, can inhibit tumor cel l growth in vitro and tumorigenesis in vivo. Some of its effects have been linked to activation of the p53 tumor suppressor; however, p53 is frequentl y mutated in tumors, particularly in the common and often therapy-resistant colon cancers. Using the human wild-type p53-expressing HCT 116 colon carc inoma cell line and HCT 116 cells with both p53 alleles inactivated by homo logous recombination, we show in the current study that resveratrol at conc entrations comparable to those found in some foods can induce apoptosis ind ependently of p53. The cell death is primarily mitochondria-mediated and no t receptor-mediated. No cells survived in cultures continuously exposed to 100 muM resveratrol for 120 hr. When compared with 5-FU, resveratrol stimul ated p53 accumulation and activity only weakly and with delayed kinetics an d neither the increased levels nor the activity affected apoptosis detectab ly. The apoptosis agonist Bax was overproduced in response to resveratrol r egardless of p53 status, yet the kinetics of Bax expression were influenced by p53. Remarkably, apoptosis was preceded by mitochondrial proliferation and signs of epithelial differentiation. Thus, resveratrol triggers a p53-i ndependent apoptotic pathway in HCT 116 cells that may be linked to differe ntiation. (C) 2001 Wiley-Liss, Inc.