Antitumor Activity of Abnormal Cannabidiol and Its Analog O-1602 in Taxol-Resistant Preclinical Models of Breast Cancer

Abstract

Cannabinoids exhibit anti-inflammatory and antitumorigenic properties. Contrary to most cannabinoids present in the Cannabis plant, some, such as O-1602 and abnormal cannabidiol, have no or only little affinity to the CB1 or CB2 cannabinoid receptors and instead exert their effects through other receptors. Here, we investigated whether the synthetic regioisomers of cannabidiol, abnormal cannabidiol, and a closely related compound, O-1602, display antitumorigenic effects in cellular models of breast cancer and whether it could reduce tumorigenesis in vivo. Several studies have shown the effects of cannabinoids on chemotherapy-sensitive breast cancer cell lines, but less is known about the antitumorigenic effects of cannabinoids in chemotherapy-resistant cell lines. Paclitaxel-resistant MDA-MB-231 and MCF-7 breast cancer cell lines were used to study the effect of O-1602 and abnormal cannabidiol on viability, apoptosis, and migration. The effects of O-1602 and abnormal cannabidiol on cell viability were completely blocked by the combination of GPR55 and GPR18-specific siRNAs. Both O-1602 and abnormal cannabidiol decreased viability in paclitaxel-resistant breast cancer cells in a concentration-dependent manner through induction of apoptosis. The effect of these cannabinoids on tumor growth in vivo was studied in a zebrafish xenograft model. In this model, treatment with O-1602 and abnormal cannabidiol (2 µM) significantly reduced tumor growth. Our results suggest that atypical cannabinoids, like O-1602 and abnormal cannabidiol, exert antitumorigenic effects on paclitaxel-resistant breast cancer cells. Due to their lack of central sedation and psychoactive effects, these atypical cannabinoids could represent new leads for the development of additional anticancer treatments when resistance to conventional chemotherapy occurs during the treatment of breast and possibly other cancers.

GPR55 Receptor Activation by the N-Acyl Dopamine Family Lipids Induces Apoptosis in Cancer Cells via the Nitric Oxide Synthase (nNOS) Over-Stimulation

“…In all cell lines, except MCF-10A and U-87MG, DHA-DA cytotoxicity was at least partially blocked by both of the two GPR55 antagonists used, indicating that GPR55 is a cell line independent target for cell death induction by this compound ( Figure 5 ). These data agree with the literature data on the GPR55 receptor expression in these cell lines [ 4 , 37 , 38 , 39 , 40 , 41 ].…”

The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

“…This agrees with Abn-CBD preserving hepatocytes proliferation without inducing tumorogenesis. Interestingly, Abn-CBD has been reported to have anti-tumoral activity rather than promoting uncontrolled proliferation (47,48). Given that Abn-CBD also decreased IL-6 levels in our mice, the beneficial effects of Abn-CBD on preserving hepatocytes proliferation might be mediated through reductions in IL-6 levels.…”

Anti-proliferative and cytotoxic effect of cannabidiol on human cancer cell lines in presence of serum

“…There are also other studies where cancer cells were cultured with 10% FCS and treated with CBD or other synthetic CBD-like molecules. The results of these studies showed that CBD (5–20 μg/mL) reduced the viability of cancer cells and also had effects on other survival variables [ 6 – 8 , 16 ]. The cell lines used in these studies being different to the ones used in our study, could account for the different results observed.…”