APOPTOSIS MEDIATES THE SELECTIVE TOXICITY OF CAFFEIC ACID PHENETHYL ESTER (CAPE) TOWARD ONCOGENE-TRANSFORMED RAT EMBRYO FIBROBLAST CELLS

The active component of the folk medicine propolis, caffeic acid phene thyl ester (CAFE), displays selective toxicity toward cloned rat embry o fibroblast (CREF) cells transformed by a spectrum of diverse acting oncogenes. identification of the mode of action of CAFE should provide useful information for possible applications of this compound for can cer therapy. The present study uses a series of on reverted and CAPE-r esistant oncogene transformed CREF cells to investigate the mechanism underlying the increased sensitivity of transformed cells to CAFE. A d irect relationship exists between the cytotoxic effects of CAPE and th e induction of DNA fragmentation and apoptosis. DNA degradation into n ucleosomal fragments and apoptotic shifts in DNA cell cycle profiles o ccur in CAPE-treated CREF cells transformed by wildtype 5 adenovirus ( Ad5), a mutant Ad5 (H5hr1), the wild-type Ad5 EIA transforming gene, v -si c, Ha-ras and the human papilloma virus type 18 transforming genes (HPV-18). In contrast, untransformed CREF cells, human fibroblast exp ression library-induced morphological revertants of Ad5- and v-src-tra nsformed CREF cells, and Krev-1 expressing revertant Ha-ras-transforme d CREF cells nl resistant to CAFE-induced toxicity and apoptosis. Simi larly, mutant Ad5-transformed CREF cells selected by step-wise growth in increasing concentrations of CAFE are resistant to growth inhibitio n and apoptosis induced by CAFE. These findings indicate that expressi on of the transformed phenotype by rodent cells evokes sensitivity to CAFE induced toxicity through apoptosis. The acquisition of CAFE sensi tivity in rodent cells is independent of the mode of action of the onc ogenic agent. CAFE may prove useful as an antiproliferative agent in c ancel cells transformed by mechanistically diverse acting oncogenes.