AbstractCaffeic acid phenethyl ester (CAPE), which is derived from the propolis of honeybee hives, has been shown to block tumor promotion and to have toxic effects on several cancer cells. The mechanism of the anti–tumor promotion activity of CAPE is unclear, however. In this study, we found that CAPE suppressed 12‐O‐tetradecanoylphorbol‐13‐acetate–induced cell transformation and induced apoptosis in mouse epidermal JB6 Cl 41 cells. No difference in induction of apoptosis was observed between normal lymphoblasts and sphingomyelinase‐deficient cell lines. Although CAPE treatment of two p53 mutant tumor cell lines, NCI‐H358 and SK‐OV‐3, and p53‐deficient (p53−/−) cells caused the cleavage of caspase‐3 as well as DNA fragmentation, caspase‐3 cleavage was seen early (at 6 h) only in cells expressing wild‐type p53 (p53+/+) and Cl 41 cells. These results suggested that p53 may be involved in the early stage of CAPE‐induced apoptosis. The p53‐dependent transcription activation occurred 2 h after treatment with CAPE and reached a maximum at 6 h in Cl 41 p53 DNA‐binding sequence stable transfectant cells. In addition, phosphorylation of p53 at serine 15 and serine 392 was induced in Cl 41 cells within 6 h after treatment with CAPE. Therefore, CAPE may induce apoptosis through p53‐dependent and p53‐independent pathways and its anti–tumor promotion activity may have occurred through the induction of apoptosis. © 2001 Wiley‐Liss, Inc.