Perillyl alcohol induces c-Myc-dependent apoptosis in Bcr/Abl-transformed leukemia cells

Bcr/Abl-transformed cells strongly resist apoptosis induced by most chemotherapy agents. However, in Bcr/Abl-transformed cells the monocyclic monoterpene, perillyl alcohol (POH), induces G0/G1 arrest and apoptosis without affecting Bcr/Abl expression or activity. The primary effect of POH is to cause growth arrest while apoptosis is a consequence of this arrest. Since Bcr/Abl induces constitutive expression of c-Myc, which is necessary for cell cycle transit from G1 into the S phase, we tested whether POH causes growth arrest by inhibiting expression of c-Myc. However, in POH-arrested Bcr/Abl-transformed cells, expression of c-Myc RNA and protein was not affected. Because expression of c-Myc during growth arrest can lead to apoptosis, we examined the role of c-Myc in POH-induced apoptosis. c-Myc induces expression of the ornithine decarboxylase (ODC) gene, which synthesizes polyamines that are necessary for cell growth. Myc-induced apoptosis operates through ODC and can be prevented with the ODC inhibitor, alpha-difluoromethylornithine (DFMO). We report that DFMO strongly protects cells from POH-induced apoptosis. These results show that in Bcr/Abl-transformed cells, POH activates a Myc-ODC apoptotic pathway that is not protected by the Bcr/Abl antiapoptotic mechanism.