COX-2 and PPAR-gamma confer cannabidiol-induced apoptosis of human lung cancer cells.

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Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M, Hinz B

COX-2 and PPAR-gamma confer cannabidiol-induced apoptosis of human lung cancer cells.

Mol Cancer Ther. 2013 Jan;12(1):69-82. doi: 10.1158/1535-7163.MCT-12-0335. Epub 2012 Dec 7.

PubMed ID

23220503 [ View in PubMed

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Abstract

The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-gamma 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-gamma antagonist), and siRNA targeting COX-2 and PPAR-gamma. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-gamma mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-gamma 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-Delta(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-gamma to the nucleus and induced a PPAR-gamma-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-gamma 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-gamma and a subsequent nuclear translocation of PPAR-gamma by COX-2-dependent PGs.