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Cannabinoids antitumor activity in humnan cancers

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Abstract

The substantial therapeutic properties of the Cannabis plant have been known since antiquity, while recently it has been “rediscovered” and applied in many diseases. The most studied active constituent in Cannabis is THC, which was the first cannabinoid to be identified and isolated. This discovery paved the way for research focused on the molecular pathways of various cannabinoids and their receptors. Cannabinoids are divided into phytocannabinoids, endogenous endocannabinoids, and synthetic cannabinoids. More than 60 phytocannabinoids have been identified within the Cannabis plant and these phytocannabinoids mediate their actions mostly through two G-coupled receptors (GPCR), CB1 and CB2 which comprise what is conceived today as the human endocannabinoid signaling system. Cannabinoids have been proposed to have a therapeutic potential for various diseases, including Multiple sclerosis, Alzheimer's disease, Epilepsy, Glaucoma, Crohn's disease and has therefore been applied as a therapeutic drug in many countries. Intriguingly, cannabis palliative effects in oncology have been well established and cannabinoids are currently used in cancer patients for inhibition of chemotherapy-induced nausea and vomiting, as well as for appetite stimulation and pain reduction. Additionally, in the last decade accumulating evidence indicates that cannabinoids might have antitumor effects. Several studies demonstrated regression of different cancer types, such as glioma, breast cancer and skin carcinoma. These effects were further investigated in vitro, in various cancer cell lines, and revealed pro-apoptotic and anti-proliferative response to cannabinoids, as well as inhibition of invasion and migration. However, the medical use of Cannabis remains rather limited, due to a large number of active compounds, which together with variability among different strains and cultivation methods impairs our ability to predict the specific clinical effect and determine the recommended dose. Therefore, there great promise lies in investigating the vast number of phytocannabinoids and the distinct antitumor effects they might have. Our lab has developed deep expertise in the areas of GPCR, cancer research as well as drug uptake and resistance mechanisms. Utilizing these techniques and the components available to us we investigate the pharmacological significance of cannabinoids in cancer. In order to select the ideal cannabinoid for each type of cancer, we are launching, a genome wide screen, testing the antitumor activity of distinct cannabinoids monitoring: anti-proliferative effects (cell cycle arrest), decreased viability, apoptosis and migration. The specific mechanism by which this antitumor effect occurs may involve the CB1 and CB2 receptors, as well as other GPCRs. However, using a whole genome silencing approach, we screen for novel receptors and protein candidates, which may regulate the cannabinoid antitumor effects. This research has the capacity to dramatically forward our basic understanding of the Cannabinoid mechanism of action and establish the optimal treatment strategy for cancer patients thus paving the way towards personalized medicine.
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