Cannabidiol oxidation product HU-331 is a potential anticancer cannabinoid-quinone: a narrative review

Abstract

Cannabidiol and related cannabinoids are under exploration for the treatment of a number of disease states. The cannabinoid-quinone HU-331 has been studied as a potential anticancer therapeutic. Previous studies provide evidence that HU-331 displays anticancer activity without some of the known adverse events associated with traditional anticancer agents. In this brief review, we will explore the literature related to the activity of HU-331 in purified systems, cancer cell lines, and animal models. For example, HU-331 displays inhibitory activity against human topoisomerase IIα, a known anticancer drug target. Further, in multiple cell model systems, the IC50 value for HU-331 was less than 10 μM. In addition, mouse model systems demonstrate the ability of HU-331 to shrink tumors without causing cardiotoxicity. In addition, we will briefly review the activity of some key analogs and derivatives of HU-331 for various disease states. Taken together, the published studies support further exploration of HU-331 for the treatment of cancer and possibly other disease states.

Characterizing the degradation of cannabidiol in an e-liquid formulation

“…Both peaks were classified as hydroxy-cannabielsoin (OH-CBE) due to diagnostic fragment ions at m/z 205.1224 and m/z 135.0492. In addition, cannabidiol hydroxyquinone (HU-331), an established oxidation product of CBD 14 , was also identified and confirmed by comparison with an authentic standard.…”

“…CBE, originally identified as a metabolite of CBD in rat liver 25 , 26 , and OH-CBD and diOH-CBD cannabinoids, also known metabolites of CBD in mammals 27 , were found to increase in CBD e-liquids under stress conditions (40 °C/75% RH). In contrast, HU-331, a reported oxidation product of CBD 14 , deviated from this trend and was increased in the samples kept at 4 °C and ambient temperature in the dark (Supplementary Fig. S9 ), indicating the thermal and photo-lability of HU-331.…”

“…Temperature also affects the degradation of CBD in solution 9 , 13 . CBD oxidizes on exposure to air, forming its hydroxyquinone (HU-331) and potentially other products 14 – 16 . While published studies have demonstrated, using high-performance liquid chromatography (HPLC) 8 , 9 , 13 , that other compounds are formed by the breakdown of CBD their identities have not been confirmed.…”

Synergistic Interactions of Cannabidiol with Chemotherapeutic Drugs in MCF7 Cells: Mode of Interaction and Proteomics Analysis of Mechanisms

“…DNA Topoisomerase II β and α ( TOP2B and TOP2A ) were significantly downregulated in CBD-treated MCF7 cells compared to the controls, with FC = −1.25 and −0.72, respectively ( Table 3 and Supplementary File 2 ). Previously, CBD derivatives such as HU-331 displayed selective inhibition to topoisomerase II isoforms via non-competitive inhibition of their ATPase activity [ 31 ]. Here, we report the inhibition of TOP2 isoforms in CBD-treated MCF7 cells for the first time, as an additional cytotoxic mechanism, along with the aforementioned downregulation of CDK-6- , MCM2- , and UBE2C -encoded proteins.…”

“…These are all suggestive of CBD’s impacts on the mitochondrial processes and energy production in cancer cells, where holistic multi-omics investigations are warranted in order to understand the underlying mechanisms. Other potential targets for CBD in cancers—such as cyclin-dependent kinases (CDK) and topoisomerases—are not well explored, despite the displayed selective inhibition of topoisomerase II by CBD derivatives such as HU-331 [ 31 ]. CBD’s anti-cancer mechanisms, its antiproliferative and pro-apoptotic effects, and its inhibitory effects on cancer metastasis, invasion, and migration were summarised in recent reviews [ 6 , 7 , 9 ].…”