A Research Project on The Potential Broad-Spectrum Anti-Proliferative Activity of CB1/CB2 Activation

Cannabinoids have long been known for their therapeutic potential when it comes to the prevention & treatment of various types of cancer. While much of the related body of research focuses on the more direct pharmacokinetics of these compounds in relation to the inhibition of various cancer-related enzymes responsible for proliferation, there is also evidence that Cannabinoids may modify how the body uptakes, metabolizes, and/or stores carbohydrates, particularly Glucose, through the activation of CB1 and CB2 Cannabinoid receptors, potentially giving Cannabinoids broad-spectrum anti-proliferative activity. Broad-spectrum treatments are of great value due to the inherent limitations of tumor-specific enzyme targeting, which make them effective only against very specific types of cancer.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171598/ Cannabinoids as therapeutic agents in cancer: current status and future implications
https://meshb.nlm.nih.gov/#/record/ui?name=Cannabinoid+Receptors Cannabinoid Receptors


Cancer is a group of diseases characterized by abnormal, rapid cell division and tissue growth which causes death through various means depending on the particular type of cancer. In most cases, cancer kills when masses of cancerous tissue invade key organs through a process known as metastasis; the detachment of cancer cells from malignant tumors and their entry into the lymph or bloodstream. Due to the abnormal and rapid growth of cancer tissue, cancer cells have an energy demand that differs from that of healthy cells. While normal cells, under normal circumstances, use mitochondrial respiration to generate energy (unless they are deprived of Oxygen in which case they switch to anaerobic forms of metabolism), cancer cells, even in the presence of adequate oxygen, rely primarily on the process of anaerobic Glycolysis to generate energy. Anaerobic glycolysis, which converts Glucose to lactate, is characterized by high glucose consumption and high lactic acid production. In cancer, this elevated glucose consumption is referred to as glucose addiction.


http://scienceline.ucsb.edu/getkey.php?key=989 How does cancer kill a person? - USCB Science Line
https://www.ncbi.nlm.nih.gov/pubmed/26504932 Glucose Addiction in Cancer Therapy: Advances and Drawbacks
https://en.wikipedia.org/wiki/Anaerobic_glycolysis Anaerobic Glycolysis

Due to the so-called “Glucose addiction” that is universally demonstrated by cancer cells, there has been a substantial body of research focused on the stimulation or inhibition of various parts of the glucose metabolism pathway as a means of cancer therapy. These therapies, including the adjuvant use of “Ketogenic” diets, the inhibition of key tumor-specific glucose transporters (GLUTs), the inhibition of enzymes involved in glycolysis and gluconeogenesis, etc. have proven quite promising. When healthy cells are deprived of Glucose, signals are sent to the liver causing ketone bodies to flow to the extra-hepatic tissue where they are used as fuel in the metabolic process of ketolysis. Because cancer cells show reduced expression of the enzymes responsible for ketolysis, data suggest that glucose starvation & dietary ketosis leads to significantly elevated levels of oxidative stress in cancer cells. Oxidative stress is defined as an imbalance between the production of reactive oxygen species (free radicals) including Superoxide (O2-) and Hydrogen peroxide (H2O2) and antioxidant defenses including Superoxide Dismutase (SOD). This increase in reactive oxygen species stimulates pro-apoptotic responses mediating programmed cell death in cancer cells while limiting apoptosis of healthy, non-cancerous cells.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867238/ Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes
https://www.ncbi.nlm.nih.gov/pubmed/20009288 Glucose deprivation-induced metabolic oxidative stress and cancer therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2129159/ Metabolic Effects of the Very-Low-Carbohydrate Diets
https://www.ncbi.nlm.nih.gov/pubmed/10693912 What is oxidative stress?
https://en.wikipedia.org/wiki/Superoxide_dismutase Superoxide Dismutase
https://www.ncbi.nlm.nih.gov/pubmed/17786631 Reactive oxygen species in mitochondria-mediated cell death
https://www.ncbi.nlm.nih.gov/books/NBK26873/ Programmed Cell Death (Apoptosis)

Another potentially promising glucose related therapy for cancer treatment is Insulin Potentiation Therapy. Due to the widely known fact that many, if not all cancer cells have elevated levels of Insulin receptor sites Insulin Potentiation Therapy is thought to potentiate existing cancer therapies by 1) improving the site-specific targeting of chemotherapy drugs, 2) reducing blood glucose levels by stimulating glucose uptake by muscle cells, and 3) Increasing glucose-addiction in cancer cells. One problem with Insulin Potentiation Therapy is its potential side-effects and potential for misuse. Insulin is tightly associated with the progression of cancer cells via its general effects on cell proliferation as well as (likely) its effect of promoting glucose uptake by cells (although the complex mechanisms involved in insulins role in tumor growth are not yet fully understood).


https://www.ncbi.nlm.nih.gov/pubmed/22649741 Low-dose chemotherapy with insulin (insulin potentiation therapy)
https://www.omicsonline.org/insulin-potentiation-therapy-in-the-treatment-of-malignant-neoplastic-diseases-a-three-year-study-1948-5956.1000117.php?aid=5970 Insulin Potentiation Therapy in the Treatment of Malignant Neoplastic Diseases: A Three Year Study
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC296896/ Elevated insulin receptor content in human breast cancer
https://www.ncbi.nlm.nih.gov/pubmed/27368923 Insulin, insulin receptors, and cancer
https://www.ncbi.nlm.nih.gov/pubmed/9575831 Insulin stimulation of glucose uptake in skeletal muscles
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021594 Insulin Promotes Glycogen Storage and Cell Proliferation in Primary Human Astrocytes
https://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-12-72 Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2

While cancer therapies have been the major focus of Cannabinoid related research in the biopharmaceutical industry, interest in the anti-diabetic properties of Cannabinoids is rapidly growing. Many Cannabinoids, including THC and CBD, have anti-diabetic properties through various pathways, some of which may make them even more valuable in the treatment of cancer due to the close relationship between diabetes, insulin, insulin receptors, the endocannabinoid system and cancer. Data suggests that Cannabinoid receptor agonists and antagonists have the simultaneous effect of both stimulating insulin secretion and lowering blood sugar, while also improving insulin resistance. One study, in particular, suggests that in Pancreatic cancer, Cannabinoids induce B-cell death by inhibiting insulin receptor activation. If this is the case, Cannabinoids may stimulate glucose uptake and lower insulin resistance in healthy cells while restricting glucose uptake and raising insulin resistance in cancer cells. Cannabinoids may have a broad spectrum therapeutic potential as an adjuvant cancer therapy outside of their direct use as anti-proliferative against specific types of cancer. In theory, by stimulating insulin secretion and lowering blood sugar while simultaneously inhibiting insulin receptor activation in cancer cells, Cannabinoids may have the same anti-proliferative action as so-called “glucose deprivation”. Studies do suggest that cannabis consumption leads to lower fasting insulin levels (suggesting an improvement in insulin resistance) as well as lower fasting blood glucose levels.


https://www.ncbi.nlm.nih.gov/pubmed/23499687 The complex effects of cannabinoids on insulin secretion from rat isolated islets of Langerhans
https://www.ncbi.nlm.nih.gov/pubmed/22234468 Blockade of CB1improves insulin resistance, lipid metabolism, and diabetic nephropathy in / mice
https://www.ncbi.nlm.nih.gov/pubmed/21564460 Cannabinoid receptor agonists and antagonists stimulate insulin secretion from isolated human islets of Langerhans
http://stke.sciencemag.org/content/5/216/ra23 Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation
https://www.ncbi.nlm.nih.gov/pubmed/23684393 The impact of marijuana use on glucose, insulin, and insulin resistance among US adults

Yet more research exists suggesting that Cannabinoids increase Cortisol levels in a dose-dependent manner, suggesting the existence of yet another pathway through which Cannabinoids may have a multi-faceted therapeutic effect against cancer. Cortisol, commonly (and incorrectly) referred to as “the stress hormone” is a steroid hormone produced by the adrenal gland released in response to stress and low blood glucose concentration. Cortisol has a profound effect on carbohydrate, lipid and protein metabolism, stimulating the catabolism (breakdown) of proteins, stimulating pro-oxidative pathways, stimulating pro-apoptotic pathways, and most importantly, stimulating energy expenditure. In theory, this increase in energy expenditure may increase the glucose-addiction expressed by cancer cells. Although glucocorticoids increase glycogen synthesis in the liver, they are generally catabolic in adipose and skeletal muscle. Cortisol has permissive action on glucagon, stimulating Glycogenolysis (the breakdown of glycogen) and proteolysis (the breakdown of proteins or peptides into amino acids by the action of enzymes). According to a study carried out by Thaddeus S Block, Tiffany I Murphy, Pamela N Munster, Dat P Nguyen, and Frank J Lynch; “ it was observed that GR expression varies by tumor type. Among the tumors with an overall high degree of GR staining, some tumors were consistently high staining (clear cell RCC, soft tissue sarcoma, melanoma, and cervical cancer), and others showed great variability among individual samples. Colon, gastric, and endometrial cancer have very low GR staining by intensity and H-score, with the majority of samples showing no GR expression”. If indeed the majority of tumor samples have no Glucocorticoid receptor expression, the increase in cortisol levels that result from Cannabinoid use may help further starve cancer cells of Glucose by mobilizing elevated Glycogen and reducing glycogenolysis in cancer tissue while promoting glycogenolysis in healthy tissue. When glycogen reserves are depleted and blood sugar remains low, a process called gluconeogenesis occurs, resulting in the conversion of glucogenic amino acids, glycerol, pyruvate, and lactate to Glucose. In healthy cells, the process of gluconeogenesis is sufficient to support glucose demand, however, due to its lower efficiency as well as the increased glucose demand of cancer cells, gluconeogenesis results in glucose starvation in cancer cells. The primary means of Gluconeogenesis is the conversion of Triglycerides to Glycerol through the process of Triglyceride hydrolysis. Studies suggest that Cannabinoids inhibit triglyceride hydrolysis while promoting lipolysis and ketogenesis, which is potentially what leads to the elevated triglyceride levels in Cannabis users and what makes Cannabinoids beneficial in the treatment of Cachexia (weight loss and muscle wasting associated with Cancer).





https://en.wikipedia.org/wiki/Cortisol Cortisol
https://academic.oup.com/jcem/article/92/9/3553/2597859/Effects-of-Cortisol-on-Carbohydrate-Lipid-and Effects of Cortisol on Carbohydrate, Lipid, and Protein Metabolism: Studies of Acute Cortisol Withdrawal in Adrenocortical Failure
https://www.ncbi.nlm.nih.gov/pubmed/8518206 Antioxidant (And Pro-Oxidant)properties of steroids
http://www.jbc.org/content/249/17/5458.full.pdf Effects of Glucagon on General Protein Degradation and Synthesis in Perfused Rat Liver
https://www.ncbi.nlm.nih.gov/pubmed/10452680 Estimation of glycogen levels in human colorectal cancer tissue compared to healthy tissue
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946160/ Fasting: Molecular Mechanisms and Clinical Applications
https://www.livestrong.com/article/415921-what-happens-when-your-body-runs-out-of-glycogen-during-a-long-workout/ What Happens When Your Body Runs Out of Glycogen During a Long Workout?
https://www.ncbi.nlm.nih.gov/pubmed/19083209 The effects of cannabinoids on serum cortisol and prolactin in humans
https://en.wikipedia.org/wiki/Gluconeogenesis Gluconeogenesis
https://www.ncbi.nlm.nih.gov/pubmed/10098887 The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797551/ Heavy marijuana users show increased serum apolipoprotein C-III levels: evidence from proteomic analyses
https://www.researchgate.net/figure/5376841_fig8_Figure-6-Correlation-analyses-of-apoC-III-levels-with-a-triglycerides-b Correlation analyses of -III with (a) triglycerides, (b) cholesterol, (c) α-1-globulin and (d) albumin in control subjects and MJ (marijuana) abusers

One of the more well-known properties of Cannabinoids is their ability to act as an orexigenic (appetite stimulant) by stimulating the body to release Grehlin. While this property of Cannabis is already exploited in alternative cancer therapies to reduce cachexia (weight loss and muscle wasting) associated with cancer. It may very well be that this is yet another potential pathway for the modification of glucose metabolism and subsequent effect on cancer by Cannabinoids. Ghrelin is a peptide hormone which not only functions as a neuropeptide, stimulating appetite through the central nervous system but also plays a key role in the distribution and rate of use of energy, also known as energy homeostasis. Normally, hunger-induced Ghrelin secretion increases hepatic glucose production and simultaneously decreases glucose uptake in cells, however, Cannabinoid mediated Grehlin secretion only seems to decrease glucose uptake in cells without increasing hepatic glucose production. This is because activation of the CB1 receptors impairs hepatic glucose production. These effects could be similar to those of Englerin A, a recently discovered guaiane sesquiterpene that, according to some studies, has a “double-edged” effect of increasing the glucose addiction expressed by cancer cells while simultaneously blocking Glucose uptake.


https://www.ncbi.nlm.nih.gov/pubmed/17983855 Appetite and metabolic effects of ghrelin and cannabinoids: involvement of AMP-activated protein kinase
http://www.jbc.org/content/280/26/25196.full Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519076/A functional neuroimaging review of obesity, appetitive hormones, and ingestive behavior
https://en.wikipedia.org/wiki/Ghrelin Grehlin
https://en.wikipedia.org/wiki/Cachexia Cachexia
https://en.wikipedia.org/wiki/Energy_homeostasis Energy Homeostasis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574184/ Englerin A stimulates PKCθ to inhibit insulin signaling and simultaneously activate HSF1: An example of pharmacologically induced synthetic lethality
https://ccr.cancer.gov/news/inthejournals/sourbier Englerin A Delivers One-Two Punch to Kidney Cancer Cells
http://www.pnas.org/content/107/19/8501.full Ghrelin and growth hormone: Story in reverse

The broad-spectrum glucose-mediated anti-proliferative activity expressed by Cannabinoids may be significantly potentiated when combined with other, aforementioned therapies aimed at glucose starvation including but not limited to clinically monitored ketogenic diets, GLUTs, gluconeogenesis inhibitors, Glycolysis inhibitors, etc. Another promising option for the potentiation of Cannabinoid therapy is the use of pro-oxidants, more specifically, compounds that inhibit naturally occurring anti-oxidative pathways. One such example is Superoxide Dismutase or SOD. SOD is an enzyme responsible for the Superoxide dismutase is an enzyme that alternately catalyzes the dismutation of the superoxide radical (O2-) into either ordinary molecular oxygen or hydrogen peroxide. The inhibition of SOD using superoxides including Iron Superoxide and Manganese Superoxide is already known to have a positive effect on cancer treatment. Cancer cells already have low levels of SOD combined with high level;s of Superoxide Radical production, which makes them particularly susceptible to the inhibition of SOD compared to other, healthy cells. As we know, oxidative stress is a key player in the pathogenesis of numerous diseases. Furthermore, the inactivation of the p53 pathway is observed in most human cancers, with mutations in p53 occurring in at least 50% of all tumors. P53 is a protein (actually, a group of proteins) that prevents cancer formation and functions as a tumor suppressor by initiating apoptosis when DNA becomes damaged beyond the repair capabilities of DNA repair proteins. Interestingly, studies indicate a direct correlation between P53 and Oxidative Stress/SOD. Low levels of P53 leads to a reduction in oxidative stress, which may be the main factor enabling tumor survival despite high superoxide radical production and low SOD levels. The administration of superoxides not only increases SOD levels but also reactivates P53 proteins, an effect which may also be potentiated by Cannabinoids due to their suggested ability to induce deSUMOlyation of bound P53 by increasing Mdm2 and SUMO-1 protein expression.


https://www.nature.com/nature/journal/v407/n6802/full/407390a0.html Superoxide dismutase as a target for the selective killing of cancer cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942707/ Manganese Superoxide Dismutase in Cancer Prevention
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329952/ Lack of p53 Decreases Basal Oxidative Stress Levels in the Brain Through Upregulation of Thioredoxin-1, Biliverdin Reductase-A, Manganese Superoxide Dismutase, and Nuclear Factor Kappa-B
https://www.ncbi.nlm.nih.gov/pubmed/19923268 Delta(9)-THC increased both Mdm2 and SUMO-1 protein expression and induced the deSUMOylation of p53 in a cannabinoid receptor type 1 (CB(1))-receptor dependent manner
http://www.sciencedirect.com/science/article/pii/S0006295215003871 Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy

In conclusion, the tumor-specific anti-proliferative properties Cannabinoids have against certain types of cancer may be met with and potentiated by broad-spectrum anti-proliferative effects through activation of CB1/CB2 receptors and subsequent modification of metabolic pathways. This would help shed some light on the widespread cancer-preventing effects of Cannabis seemingly demonstrated by statistical data but not yet identified and isolated by medical science, including the widely known benefits of Cannabis on cancer patients suffering Cachexia. More research should be done into the anti-proliferative properties of Cannabinoids surrounding glucose metabolism, oxidative stress, and combination with existing pro-oxidant therapies already widely exploited in cancer treatment such as the use of ionizing radiation and chemotherapy, ideally in a targeted nature.