RESUMO
Cannabis has been used for various medicinal applications including, but not limited to, cancer: most commonly to treat chemotherapy-associated side effects. Cannabis is often used for its palliative effects in the form of purified cannabinoids, or as extracts. This study was conducted using two breast cancer cell lines and aimed to evaluate potential anti-proliferative "intra-entourage effects" between purified phytocannabinoids resembling the THC and CBD ratios of medicinal and recreational cannabis strains, as well as to investigate potential "inter-entourage effects" between the different ratios and the phytochemicals found in a Cannabis sativa extract. This study also aimed to evaluate the potential interaction between cannabinoids and chemotherapeutic agents. The data identified an intra-entourage effect present in the MCF-7 cells when treated with a recreational, but not a medicinal, cannabis formulation. This effect may be due to THC partially exerting its anti-proliferative effects through the estrogen receptor (ER), present in the MCF-7 cell line. Little to no intra-entourage effects were observed in the MDA-MB-231 cell line and no inter-entourage effects were observed in either cell line. The simultaneous treatment of the MCF-7 cell line with various cannabinoid formulations and the common breast cancer treatment, tamoxifen, resulted in the diminished anti-proliferative activity of tamoxifen, an effect that was more evident when combined with recreational cannabis formulations. Since cannabis is commonly used in palliative care to treat chemotherapy-associated side effects, further research is required to investigate the potential interference of various cannabis formulations to ensure that the efficacy of chemotherapeutic agents is not compromised. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-03102-1.
RESUMO
Endoplasmic reticulum (ER) stress is an imbalance between the protein-folding load and capacity of ER. It can be induced by various physiological conditions, activating the unfolded protein response (UPR) to re-establish homeostasis, promoting cell survival. Under severe or chronic stress, apoptosis is induced. Normal cells generally do not experience continuous ER stress induction. The stressful conditions experienced in the tumor microenvironment facilitate chronic ER stress and UPR activation, which plays a pivotal role in tumour survival. Exacerbation of pre-existing ER stress can trigger cancer cell death, with a minimal effect on normal cells. Current literature suggests that cannabinoid treatment may induce cancer cell death via ER stress; however, little is known about the mechanisms of induction. This study proposed that cannabidiol (CBD) mechanism occurred through the influx of Ca2+ via the TRPV1 receptor, and increasing reactive oxygen species (ROS) production affects protein folding and induces ER stress. ER stress was induced, and detection and quantification were completed using Thioflavin T staining and GRP78 by western blot analysis. The effect of cannabinoid treatment on ROS production and Ca2+ influx was measured. CBD was the most potent ER stress inducer, significantly increasing Ca2+ and ROS accumulation. Concomitant treatment with CBD and an antioxidant significantly increased cell viability and decreased ER stress induction in the MCF7 cell line. Concomitant treatment with a TRPV1 antagonist increased viability in this cell line. In conclusion, the data suggested that CBD induced ER stress via Ca2+ influx through the TRPV1 receptor, thereby elevating intracellular ROS levels and disrupting protein folding.
