Many epidemiological studies, animal models and mechanistic experiments have supported the idea that docosahexanoic acid (DHA) can potentiate the efficacy of chemotherapeutic drugs in tumor cells while protecting normal tissues from excess cellular damage. This study examines whether the differential expression of protein kinase C (PKC) [delta] and [epsilon] and drug sensitivity between the normal FRC/TEX CL 4D/WT (4D) and transformed FRC/TEX CL D/v-src (src) rat colonic epithelial cells are causally related to the specific activities of either PKC [delta] or [epsilon]. Although an increased expression of PKC [delta] is caused by DHA supplementation of transformed colonic epithelial cells, none of Rottlerin, Ingenol 3-20 dibenzoate (IDB), and GF 109203X (GF), had any effect on AraC toxicity in either normal or transformed cells. The activities of PKC [delta] and [epsilon], in both cell types, was unaltered by DHA supplementation. These results show that DHA has no effect on AraC toxicity in rat colonic epithelial cells, and that the antitumor effect of AraC is neither improved by DHA nor mediated by the PKC signaling pathway.