title: COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.
abstract: The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ 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-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ 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-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ 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-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.
authors.affiliation: Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Ramer
authors.forename: Katharina
authors.initials: K
authors.lastname: Heinemann
authors.forename: Jutta
authors.initials: J
authors.lastname: Merkord
authors.forename: Helga
authors.initials: H
authors.lastname: Rohde
authors.forename: Achim
authors.initials: A
authors.lastname: Salamon
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hinz
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002185:Cannabidiol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009578:Nitrobenzenes / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D047495:PPAR gamma; D011453:Prostaglandins; D034741:RNA, Small Interfering; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D002185:Cannabidiol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human