COX-2 and PPAR-γ 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.


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.

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cannabidiol / pharmacology*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Female
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Nitrobenzenes / pharmacology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Prostaglandins / biosynthesis
  • Prostaglandins / physiology
  • RNA, Small Interfering / genetics
  • Sulfonamides / pharmacology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Antineoplastic Agents
  • Cyclooxygenase 2 Inhibitors
  • Nitrobenzenes
  • PPAR gamma
  • Prostaglandins
  • RNA, Small Interfering
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cannabidiol
  • Cyclooxygenase 2
  • PTGS2 protein, human