The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 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 cannabidiol was suppressed by NS-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 mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD 2 and 15-deoxy-D 12,14 -PGJ 2 (15d-PGJ 2 ) 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); 69-82. Ó2012 AACR.
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