Researchers review different varieties of cannabinoids, the signaling pathways they affect, and their role in different types of cancer.
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In a high-rated paper published in 2014 in Oncotarget, researchers from India’s Sanjay Gandhi Post Graduate Institute of Medical Sciences and the United States’ Ohio State University reviewed cannabinoids, their role in different types of cancer, and the signaling pathways they affect. Today, this paper currently presents with an Altmetric Attention score of 200.
“In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities.”
Cannabinoids and Receptors
“[The] Cannabis sativa plant has been used for several hundreds of years both recreationally and medicinally.”
Researchers trace the earliest archaeological evidence of cannabis medical use back to ancient China, during the Han Dynasty. The use of this plant was recommended for rheumatic pain, constipation, disorders of the female reproductive tract, and malaria, among other conditions. Cannabis sativa contains three major classes of bioactive molecules; flavonoids, terpenoids, and 100+ types of cannabinoids.
Cannabinoids are a family of complex chemicals that activate and bind to two receptors in mammals named central cannabinoid receptor one (CB1) and peripheral cannabinoid receptor two (CB2). These receptors are found abundantly throughout the central nervous system and immune system.
“CB1/2 receptors are also responsible for proliferation, motility, invasion, adhesion and apoptosis of cancer cells both in vitro and in vivo.”
CB1 and CB2 receptors have been used as targets for the treatment of various diseases, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease, neuropathic and inflammatory pain, glaucoma, multiple sclerosis, cardiovascular disorders, obesity, and more. Today, in addition to inhibiting nausea and emesis, stimulating appetite, improving mood, and relieving pain and insomnia that cancer patients face, cannabinoids used in the targeted killing of tumor cells has been a major discovery in cancer treatment.
“In this review article we focused on the role of cannabinoids in different cancer types and the respective signaling pathways.”
“Endogenous cannabinoids which are produced in our body include lipid molecules containing long-chain polyunsaturated fatty acids, amides, esters and ethers that bind to CB1 or CB2 receptors.”
Endocannabinoids act primarily as neuromodulators, or reverse messengers, which can affect the release of neurotransmitters. They also play important role in regulating inflammation, insulin, and fat and energy metabolism, which affects our mood, appetite, pain sensation, inflammation response, and memory.
“Phytocannabinoids are only known to occur naturally in significant quantities in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes.”
Over 120 phytocannabinoids are capable of interacting within the body’s own biological systems because their structures and behaviors mimic those of endocannabinoids (cannabinoids that are synthesized by our own bodies). The most prevalent natural cannabinoids are delta-9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), and cannabinol (CBN).
“Synthetic cannabinoids are classified on the basis of chemical structure of molecules and they are capable of a more selective activation of cannabinoid receptors .”
The researchers explain that synthetic cannabinoids have been used extensively in pharmacology to gain better insight about their action in order to evaluate the potential use of cannabinoids clinically.
Within the synthetic category, classical cannabinoids are compounds isolated from the Cannabis sativa plant or its synthetic analogs. Nonclassical cannabinoids “are a family of AC-bicyclic and ACD-tricyclic cannabinoid analogs.” Aminoalkylindoles are non-cannabinoid molecules given cannabis-mimicking capabilities. Eicosanoids are compounds that can enhance or inhibit physiological and pathophysiological responses. These lipid mediators also have an affinity for CB1 and CB2 receptors.
Cannabinoids in Cancer
Multiple studies have shown that THC, CBD, and synthetic cannabinoids can inhibit breast cancer cell proliferation and drive them toward apoptosis.
“It [breast cancer] is classified into three main subtypes according to their molecular profiles: hormone receptor-positive, HER2-positive (ErbB2-positive, a member of EGFR family) and triple-negative tumors [42-43]. Cannabinoid-based medicines have been useful for the treatment of these three breast cancer subtypes.”
In prostate cancer, CB1 and CB2 expression levels are often higher in prostate cancer tissues and several cell lines compared to normal prostate epithelial cells. Studies have found that cannabinoids have either induced cell death or activated pathways that lead to growth inhibition and increased patient survival.
Preclinical cancer models have shown that cannabinoids can alter gene expression, block enzymes, inhibit signaling pathways, and induce apoptosis in mice with lung cancer. In skin and pancreatic cancers, researchers have found that the activation of CB1/2 receptors induced the apoptotic death of tumorigenic cells, without affecting the normal cells. In bone cancer studies, researchers found that cannabinoids reduced pain and bone loss in mice.
“Cannabinoids could halt tumor development without side effects via specific targeting of CB1/CB2 receptor.”
Cannabinoids have anti-tumorigenic properties in glioma, lymphoma, oral cancers, and thyroid carcinoma. In young people, marijuana smoking has been found to increase the incidence of head and neck cancer, however, cannabinoids have anti-tumor properties.
“Cannabinoids exert a direct anti-proliferative effect on tumors of different origin.”
Given that cannabinoid receptors are often demonstrated to be expressed higher in tumor cells than in normal cells, cannabinoids are more specific to cancer cells than to normal cells. The researchers conclude their review by noting that it is important to identify which cannabinoids are most compatible with an individual cancer or disorder to have the greatest impact on patient outcome.
“It is important to understand which of the cannabinoid receptors are expressed and activated in different tumors as each receptor follows a different signaling mechanism.”
Years after this paper was published, subsequent studies have confirmed and expanded on many ideas mentioned in this review, including the regenerative and pharmacological effects of THC, synthetic cannabis used to treat thrombosis, increased expression of CB2 potentially linked to colon cancer, experiments with cannabis extracts, synergistic combinations of cannabinoids, and much more.
Click here to read the full scientific review, published in Oncotarget.
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