Induction of the apoptosis-promoting protein Bak by perillyl alcohol in pancreatic ductal adenocarcinoma relative to untransformed ductal epithelial cells

Perillyl alcohol has antitumor activity toward pancreas and other cancerswith low toxicity. Here, we have investigated the mechanism of actionresponsible for the differential sensitivity of malignant versusnon-malignant pancreatic cells to the drug. We report that the rate ofapoptosis is over 6-fold higher in perillyl alcohol-treated pancreaticadenocarcinoma cells than in untreated cells, and that the effect ofperillyl alcohol on pancreatic tumor cells is significantly greater thanits effect on non-malignant pancreatic ductal cells. Moreover, the perillylalcohol-induced increase in apoptosis in all of the pancreatic tumor cellsis associated with a 2- to 8-fold increase in the expression of theproapoptotic protein Bak, but Bak expression is not affected by perillylalcohol in non-malignant cells. Thus, the antitumor activity of perillylalcohol toward pancreatic cancers may be due to preferential stimulation ofBak-induced apoptosis in malignant versus normal cells. Bak may, therefore,be a useful biomarker for the chemopreventive and therapeutic effects ofperillyl alcohol.