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-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.

Molecular Targets of Cannabidiol in Neurological Disorders

“…Here, the protective effects of CBD in an Aβ-induced neuroinflammatory mouse model were abolished by a PPARγ antagonist, but no evidence was given as to whether this was a direct or indirect effect [198]. CBD can also positively modulate COX via increased mRNA and protein expression of PPARγ and COX2, which also suggests that a COX2-generated increase in PGD 2 and 15d-PGJ 2 could underlie PPARγ activation in addition to any direct activation of PPARγ by CBD [18,54,93]. A possible mechanism for this is suggested by the observation that NRF2 can increase PPARγ expression as CBD can activate NRF2 [79,199,200].…”

“…Conversely, a different study showed that 318 μM CBD had no effect upon the in vitro activities of COX1 and COX2 (Table 2) [69], while in vivo administration of CBD had no effect upon COX2 activity in tumor tissue [68] (Table 2). However, a further study suggested that CBD may modulate COX2 activity by stimulating transcription and/or translation in some subtypes of cells [18]. While the concentrations described above are unlikely to be physiologically achievable, a more recent study suggested that 10 μM CBD increased arterial vasorelaxation in diabetic Zucker rats, which was associated with COX1 and COX2 stimulation via an allosteric mechanism [93].…”

“…The peroxisome proliferator-activated receptor (PPAR) γ, otherwise known as the glitazone receptor, is thought to be responsible for lipid storage and glucose metabolism [18], and some anticancer effects of CBD are thought to by mediated through interaction with PPARγ. In human A549 and A460 cancer cell lines, a time-dependent increase in PPARγ mRNA was observed following the application of CBD (1-3 μM).…”

“…CBD has also been shown to inhibit tumor cell viability; cell death assays revealed IC 50 values of 3.47 μM (A549) and 2.80 μM (A460). A complete loss of tumor cell viability was observed at 8 μM (A549) and 7 μM (A460) [18]. Interestingly, these effects on tumor cells were not prevented by pharmacological tools acting at CB 1 R, CB 2 R, or transient receptor potential (TRP) vanilloid-type 1 (TRPV1).…”

“…CBD has been shown to upregulate and activate PPARγ [18,54], and therefore it may be able to replicate the effects of pioglitazone.…”