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

Abstract

-Metastases are known to be responsible for approximately 90% of breast cancer-related deaths. 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). These changes were confirmed by real-time RT-PCR analyses. Taken together, the results obtained here demonstrated that i) CBDA had dual inhibitory effects on COX-2 through down-regulation and enzyme inhibition, and ii) CBDA may possess the ability to suppress genes that are positively involved in the metastasis of cancer cells in vitro.

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

“…Cannabidiolic acid (CBDA), being a C3 -carboxyl derivative of CBD (2,4-dihydroxy-3-[(1R, 6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-[alpha]-6-pentylbenzoic acid), acts as a selective COX2 and prostaglandin endoperoxide synthase inhibitor and exhibits anti-inflammatory properties in human breast cancer cells [113]. It has been suggested that its action may be due to a weak affinity for CB1 and CB2 receptors ( Table 2) [114].…”

Cannabidiolic acid dampens the expression of cyclooxygenase-2 in MDA-MB-231 breast cancer cells: Possible implication of the peroxisome proliferator-activated receptor β/δ abrogation

“…CBDA can interfere with COX-2 expression in MDA-MB-231 breast cancer cells, a highly aggressive triple-negative breast cancer cell line, and that CBDA exhibits selective inhibition of COX-2, as shown with purified COX-2 used as an enzyme source (Takeda et al, 2008(Takeda et al, , 2014a(Takeda et al, , 2017Takeda, 2013;Suzuki et al, 2017). The MDA-MB-231 cell line is also an accepted model of estrogen receptor α (ERα)-negative breast cancer as the cells do not require estrogens for growth, and MDA-MB-231 cells express all the subtypes of the peroxisome proliferator-activated receptors, PPARα, PPARβ/δ, and PPARγ (Suchanek et al, 2002a(Suchanek et al, , 2002bTakeda et al, 2013Takeda et al, , 2014bHirao-Suzuki et al, 2019b).…”

“…1A), a constituent of the fiber-type cannabis plant, is a biologically active component. For example, CBDA is reported to exert anti-bacterial effects (Appendino et al, 2008), cyclooxygenase-2 (COX-2) enzyme inhibition (Takeda et al, 2008;Takeda, 2013), down-regulation of COX-2 expression (Takeda et al, 2014a(Takeda et al, , 2017Suzuki et al, 2017), and anti-nausea/emetic effects (Bolognini et al, 2013;Rock and Parker, 2013).…”

Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5‐HT1A receptor‐mediated suppression of nausea and anxiety in rats

“…However, even the limited amount of information on this phytocannabinoid that has been published suggests that it may have a wide variety of actions and effects. Thus, it has been shown to inhibit breast cancer cell migration (Takeda et al, ) and to cause a down‐regulation of COX‐2 (Takeda et al, ).…”