Cancer Therapeutic Insights COX-2 and PPAR-g Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

The antitumorigenicmechanismof cannabidiol is still controversial. This study investigates the role of COX2 and PPAR-g in cannabidiol’s proapoptotic and tumor-regressive action. In lung cancer cell lines (A549,H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiolwas suppressed byNS-398 (COX-2 inhibitor), GW9662 (PPAR-g antagonist), and siRNA targeting COX-2 and PPAR-g . Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-g mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-g mRNAwhen compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2–dependent prostaglandins (PG) among which PGD2 and 15-deoxy-D-PGJ2 (15d-PGJ2) caused a translocation of PPAR-g to the nucleus and induced a PPAR-g–dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-g in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-g and a subsequent nuclear translocation of PPAR-g by COX-2–dependent PGs.Mol Cancer Ther; 12(1); 1–14. 2012 AACR.