Targeting multiple cannabinoid anti‐tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer

Abstract

BACKGROUND AND PURPOSEThe psychoactive cannabinoid Δ 9 -tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways. EXPERIMENTAL APPROACHTo measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo. KEY RESULTSCBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD-and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo. CONCLUSIONS AND IMPLICATIONSO-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer.

The use of cannabinoids as anticancer agents

“…This effect of CBD relies -at least partiallyon the downregulation of ID-1 (transcription factor inhibitor of DNA binding-1)(McAllister et al, 2011;Murase et al, 2014;Soroceanu et al, 2012).…”

The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids

“…In a model where tumors were derived from subcutaneous implanted human lung cancer cells, full reversal of CBD-dependent antitumor activity was observed in the presence of a PPRγ antagonist (Ramer et al, 2013). Finally, it was recently demonstrated that the anti-metastatic activity of CBD in a mouse model of breast cancer was not reversed in the presence of a CB 2 receptor antagonist (Murase et al, 2014). …”

“…The ability of CBD to enhance the activity of THC was associated with the production of ROS leading to inhibition of pERK and activation of multiple caspases. In a more recent study, it was reported in a mouse model of breast cancer metastasis that CBD was more potent than THC at inhibiting the formation of lung metastatic foci (McAllister et al, 2007; Murase et al, 2014). …”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…It dampens nitric oxide (NO) production in animal models of acute and chronic inflammation (24,152,162,247,267,600,654,758), the expression of inflammatory cytokines and transcription factors [interleukin (IL)-1␤, IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-␣, interferon (IFN)-␥, CCL3, CCL4, NF-B] (39, 419), and reactive oxygen species (ROS) production (320, 767). However, in many types of cancer cells, CBD is capable of generating ROS, thereby inducing cytotoxicity or apoptosis and autophagy (478,540,543,547,552,610,862). CBD also improves mithochondrial function and enhances mithochondrial biogenesis in vivo under pathological conditions (327).…”