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.
Highlights
Cannabis has been used as a medicine throughout history to treat a variety of diseases
Due to the apparent importance of their receptors in certain cancer types, two atypical cannabinoids, abnormal CBD (Abn-CBD) and O-1602 that mediate their effects through GPR55 and GPR18, were selected in our study
While LPI seems to contribute to cancer progression and metastasis through the activation of GPR55, it was shown in a cholangiocarcinoma model that an endocannabinoid, anandamine (AEA), whose effects were not mediated through the activation of the typical CB1/CB2 receptor or vanilloid 1 receptor, suppressed cholangiocarcinoma growth by inducing apoptosis
Summary
Cannabis has been used as a medicine throughout history to treat a variety of diseases. Phytocannabinoids are produced by the plant Cannabis and target both the endocannabinoid system and other biological pathways This allows them to exert a wide array of effects both on the central nervous system and peripheral immune, cardiovascular, digestive, reproductive, and ocular systems (Chanda et al, 2019, Pertwee et al, 2010). Available cannabinoids, such as dronabinol, nabilone, and others, are approved for the treatment of cancer-related side effects such as nausea and vomiting (Steele et al, 2019). Cannabinoids have been shown to exhibit antitumorigenic properties in various preclinical cancer models (McAllister et al, 2015; Ladin et al, 2016; Blasco-Benito et al, 2018)
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