Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis

Abstract

ABSTRACT:In the present study it was revealed that cannabidiolic acid (CBDA) selectively inhibited cyclooxygenase (COX)-2 activity with an IC 50 value (50% inhibition concentration) around 2 M, having 9-fold higher selectivity than COX-1 inhibition. In contrast, ⌬ 9 -tetrahydrocannabinolic acid (⌬ 9 -THCA) was a much less potent inhibitor of COX-2 (IC 50 > 100 M). Nonsteroidal anti-inflammatory drugs containing a carboxyl group in their chemical structures such as salicylic acid are known to inhibit nonselectively both COX-1 and COX-2. CBDA and ⌬ 9 -THCA have a salicylic acid moiety in their structures. Thus, the structural requirements for the CBDAmediated COX-2 inhibition were next studied. There is a structural difference between CBDA and ⌬ 9 -THCA; phenolic hydroxyl groups of CBDA are freed from the ring formation with the terpene moiety, although ⌬ 9 -THCA has dibenzopyran ring structure. It was assumed that the whole structure of CBDA is important for COX-2 selective inhibition because ␤-resorcylic acid itself did not inhibit COX-2 activity. Methylation of the carboxylic acid moiety of CBDA led to disappearance of COX-2 selectivity. Thus, it was suggested that the carboxylic acid moiety in CBDA is a key determinant for the inhibition. Furthermore, the crude extract of cannabis containing mainly CBDA was shown to have a selective inhibitory effect on COX-2. Taken together, these lines of evidence in this study suggest that naturally occurring CBDA in cannabis is a selective inhibitor for COX-2.

Down-regulation of cyclooxygenase-2 (COX-2) by cannabidiolic acid in human breast cancer cells

“…Although we demonstrated for the first time that CBDA was a potent inhibitor of COX-2 (IC 50 = 2.2 M) purified from sheep placental cotyledons, which are a general enzyme source for screening (Cayman Chemical Company) (Takeda et al, 2008), a contradictory phenomenon, in which CBDA exhibited a very weak inhibitory potential on COX-2, was recently reported (Ruhaak et al, 2011). Since this research group and we used the same enzyme source, this discrepancy may have been caused by differences in the experimental conditions or purity of CBDA.…”

“…The specific use of the acidic cannabinoid as an active pharmaceutical ingredient has not yet been achieved because CBDA is recognized as the pharmacologically inactive form (Yamauchi et al, 1967;Razdan, 1986;Burstein, 1999). However, recent studies including ours demonstrated that, in addition to CBD, CBDA by itself exhibits biological actions, such as antibacterial effects (Appendino et al, 2008), the inhibition of cyclooxygenase-2 (COX-2) (Takeda et al, 2008), and anti-nausea/emetic effects (Bolognini et al, 2013;Rock et al, 2013).…”

“…Cyclooxygenase-2 (COX-2) is involved not only in inflammatory processes, but also in the metastasis of cancer cells; it is expressed in 40% of human invasive breast cancers. To comprehensively analyze the effects of cannabidiolic acid (CBDA), a selective COX-2 inhibitor found in the fiber-type cannabis plant (Takeda et al, 2008), on COX-2 expression and the genes involved in metastasis, we performed a DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are invasive breast cancer cells that express high levels of COX-2, treated with CBDA for 48 hr at 25 μM. The results obtained revealed that COX-2 and Id-1, a positive regulator of breast cancer metastasis, were down-regulated (0.19-fold and 0.52-fold, respectively), while SHARP1 (or BHLHE41), a suppressor of breast cancer metastasis, was up-regulated (1.72-fold) and CHIP (or STUB1) was unaffected (1.03-fold).…”

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

“…However, there are only a few in vivo investigations addressing cannabidiol's impact on COX-2 in cancer tissue showing no interference with COX-2 protein levels in experimental glioma (39) and colon cancer (40). About the impact of cannabinoids on COX-2 activity in cell-free assays, several cannabinoids including cannabidiolic acid (41), cannabigerol, and cannabigerolic acid (42) have been shown to profoundly inhibit COX-2, whereas cannabidiol tested at 100 mmol/L (41) or 300 mmol/L (42) failed to elicit such response or only slightly suppressed COX-2 at 100 mmol/L (39).…”

The Endocannabinoid System and its Modulation by Phytocannabinoids

“…Further interactions can be predicted on the basis of the capability of both polyunsaturated endocannabinoid-like mediators and plant cannabinoids to inhibit, or to be oxidized by, cytochrome p450 oxygenases [55,56], which, in theory, allows the latter compounds, when administered systemically, to modulate the levels of the former. Finally, CBD acid, and much less so THC acid, were reported to inhibit cycloxygenase-2 [57], thus potentially inhibiting the formation not only of prostanoids, but also of prostamides and prostaglandin-glycerol esters. However, such interactions are yet to be demonstrated in vivo.…”