cancer cell death

Medical Marijuana May Induce Cancer Cell Death, as explained by a Scientist

Medical Marijuana May Induce Cancer Cell Death, as explained by a Scientist

Gliomas are a type of brain and spinal cord tumor that arise from glia, the cells that directly support the function of neurons. This type of cancer is highly invasive and follows characteristic patterns, typically invading adjacent brain structures nearby large blood vessels via a process called angiogenesis (the formation of new blood vessels). In clinical and preclinical studies, cannabinoids have been shown to hinder the progression of gliomas by reducing tumor growth, inducing cell death, providing synergistic effects with radiotherapy, and by inhibiting angiogenesis and metastasis (spreading to other areas) of tumor cells. Some of these effects are thought to be mediated by the body’s endocannabinoid system (ECS), a group of receptors found on the surface of the cell membrane and mitochondria, while others occur through non-cannabinoid receptor interactions.

Reductions in Cancer Spread: Multiple studies have shown that cannabidiol (CBD) is capable of reducing the invasiveness of gliomas in a concentration dependent fashion. These effects do not appear to be mediated by cannabinoid receptors and seem to arise through multiple processes. One factor is CBD’s ability to inhibit the migration of cancer cells. Additionally, CBD reduces invasiveness through a decrease in the production of pro-angiogenic factors. These pro-angiogenic factors are proteins that promote the formation of new blood vessels, many of whose levels have shown to be directly correlated with cancer invasiveness[ref]Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol. 2005;144(8):1032-6[/ref].

Inducing Death of Cancer Cells:  Researchers from Spain have demonstrated the ability of THC to induce cell cancer death through such cannabinoid receptor dependent mechanisms. Specifically, the THC causes a stress response in glioma cells that leads to the accumulation of a compound called ceramide, a compound that ultimately leads to apoptosis (programmed cell death)[ref]Sánchez C, Galve-roperh I, Canova C, Brachet P, Guzmán M. Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 1998;436(1):6-10.[/ref].

This stress response kills only the cancerous cells, leaving the healthy cells unharmed. Studies using CBD have also shown its ability to kill glioma cells by increasing the production of compounds called reactive oxygen species (ROS). These ROS are a by-product of cellular respiration, the process of energy production in the form of ATP that occurs in the mitochondria. Increased levels of these molecules put additional stress on the cell and cause signaling cascades that ultimately lead to similar cell death mechanisms[ref]Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, Parolaro D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci. 2006;63(17):2057-66[/ref].

Antiproliferative Effects: In addition to inhibiting the spread of cancerous cells, cannabinoids have also been shown to induce cell cycle arrest, effectively hindering their division. Researchers have demonstrated that the administration of THC and CBD together causes synergistic effects in this curbing cancer cell proliferation[ref]Marcu JP, Christian RT, Lau D, et al. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther. 2010;9(1):180-9[/ref].

Based on these studies cannabinoids hold much therapeutic value for the treatment of gliomas due to their antitumoral action, ability to kill cancer cells, and effects on proliferation. Additionally, studies in mouse models using both THC and CBD have also been shown to have an additive effect when used in conjunction with radiotherapies, suggesting that cannabinoids could potentially enhance current cancer mitigation strategies[ref]Scott KA, Dalgleish AG, Liu WM. The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther. 2014;13(12):2955-67[/ref].


COPD

Chronic obstructive pulmonary disease (COPD) and Cannabis, as explained by a Scientist

Chronic obstructive pulmonary disease (COPD) and Cannabis, as explained by a Scientist

Chronic obstructive pulmonary disease (COPD) is an illness characterized by increased production of mucus and chronic inflammation of the airways resulting in reduced respiratory capacity. The two primary forms of COPD are chronic bronchitis, which produces a long-term cough with mucus, and emphysema, which leads to the progressive deterioration of the alveoli, the air sacs that allow for gaseous exchange in the lungs.

All smoke irritates the lungs and aggravates COPD, but vaporized or ingested cannabis could potentially provide many benefits because of its anti-inflammatory, immunosuppressant, and bronchodilating (airway opening) qualities.

Bronchodilatory effects: Studies performed in the 1970’s at the University of California Los Angeles by Donald Tashkin have shown that both inhaled and orally ingested THC produce bronchodilation for up to two hours after administration[ref]Tashkin DP, Shapiro BJ, Frank IM. Acute effects of smoked marijuana and oral delta9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. Am Rev Respir Dis. 1974;109(4):420-8.[/ref].

Further investigations by the Respiratory Pharmacology Laboratory in Paris have shown that CB1 receptor activation inhibits contraction of the smooth muscle surrounding the lungs in a concentration-dependent fashion, offering a possible mechanism for acute bronchodilation associated with cannabis intake[ref]Grassin-delyle S, Naline E, Buenestado A, et al. Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors. Br J Pharmacol. 2014;171(11):2767-77.[/ref]. Although smoked cannabis also has this effect, any kind of combustion creates other lung irritants that would be counterproductive for COPD treatment.

Suppression of the immune system: Those with COPD have a heightened immune response in the lungs and compounds in cannabis can lead to immunosuppression. Studies have shown that THC induces rapid mobilization of a specific subset of white blood cells that arise from bone marrow called myeloid-derived suppressor cells (MDSCs)[ref]Hegde VL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol. 2010;40(12):3358-71.[/ref]. These cells exert potent immunosuppressant properties by inhibiting the proliferation and activation of T-cells, a component of the body’s immune response.

Additional studies performed at the University of South Carolina School of Medicine support these findings, where they determined that the intraperitoneal (injection into the body cavity) application of THC causes changes in microRNA expression that promotes the suppression of the immune system[ref]Hegde VL, Tomar S, Jackson A, et al. Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Δ9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein α by microRNA-690. J Biol Chem. 2013;288(52):36810-26.[/ref]. Other findings using murine models have shown that intraperitoneal administration of THC results in a reduction of allergen-induced mucus production[ref]Reddy AT, Lakshmi SP, Reddy RC. Murine model of allergen induced asthma. J Vis Exp. 2012;(63):e3771.[/ref].

Anti-inflammatory effects: Cannabinoids have anti-inflammatory benefits through a variety of mechanisms. The acidic cannabinoids found in the raw plant (THCA, CBDA, etc.) have a greater anti-inflammatory capacity than their non-acidic counterparts (THC, CBD, etc.). Specifically studies by Ruhaak, et al., have shown that acidic cannabinoids are capable of inhibiting enzymes called cyclooxygenases (COX-1 and COX-2). These enzymes are responsible for the production of inflammatory molecules such as prostaglandins, which contribute to airway inflammation.

Recently studies performed at the University of Sao Paulo using cannabidiol (CBD) have also shown some potential for improving the symptoms of COPD. Using LPS, a component of the cell wall of gram-negative bacteria as an inflammatory agent, they showed the application of CBD resulted in decreased pulmonary inflammation and improvements in lung function in mouse models of inflammatory lung disease[ref]Ribeiro A, Almeida VI, Costola-de-souza C, et al. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol Immunotoxicol. 2014;:1-7.[/ref].

Other studies of terpene compounds, the aromatic components found in cannabis show anti-inflammatory benefits as well. In particular, beta caryophyllene has been shown to act as a dietary cannabinoid, attenuating inflammatory responses in various tissues in a CB2 receptor-dependent fashion[ref]Bento AF, Marcon R, Dutra RC, et al. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011;178(3):1153-66.[/ref].

Conclusion: These studies indicate that cannabis could potentially act as a means to mitigate acute attacks of airway constriction and may also act as a preventative measure for patients with COPD. However, human trials are needed to confirm some of these benefits and until restrictions on this kind of research are lifted, a deeper understanding of these mechanisms will remain poorly understood.


Chronic Pain

How Cannabis can help Chronic Pain, as explained by a Scientist

How Cannabis can help Chronic Pain, as explained by a Scientist

Since ancient times its been known that cannabis can provide relief from a variety of different types of pain.  Recent estimates show that chronic pain affects up to 7.8 million people in the United Kingdom alone and the current pharmaceutical strategies for mitigating chronic pain have led to the addiction to nearly one million of those people.  Over the counter non-steroidal anti-inflammatory drugs (NSAIDs) are not much better and can have a variety of adverse effects such as liver damage, erectile dysfunction, and potential for overdose.  The search for safer alternatives prompted research into cannabis’ effects as an analgesic and scientists are now beginning to unravel how the compounds in cannabis interact with the body to produce these effects in a less harmful and less addicting fashion than over the counter medications and prescribed pharmaceuticals.

The endocannabinoid system primarily consists of two types of receptors called CB1 and CB2, with CB1 being predominant in the central nervous system and CB2 being prevalent in the periphery. Each of these receptors plays a different role in modulating the sensation of pain at various levels of pain processing pathways.  Interestingly, some pain medications rely on the same pathways cannabis does to produce pain relief.  Acetaminophen, a common ingredient in readily available pain medications is metabolized by the body into the cannabinoid compound AM-404. The action of this compound at the cannabinoid receptor CB1 is partially responsible for acetaminophen’s anti-inflammatory and pain relieving properties[ref]Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A. The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. Eur J Pharmacol. 2006;531(1-3):280-1.[/ref].

Some types of pain manifest themselves in the form of inflammation. The CB2 receptor is a key modulator of inflammation and the processing of the pain it can cause. Compounds in cannabis such as THC, CBD, beta caryophyllene, alpha pinene, and beta myrcene bind to cannabinoid receptors and other targets to produce analgesic and anti-inflammatory effects[ref]Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099-104.[/ref].

Cannabinoid compounds, particularly the acidic versions found in the raw plant (THCA and CBDA), also exert their anti-inflammatory effects by inhibiting the enzymes that produce pro-inflammatory molecules called prostaglandins[ref]Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8.[/ref]. It has been reported that the anti-inflammatory capacity of THC, the primary psychoactive component in cannabis is up to twenty fold to that of aspirin and up to twice that of hydrocortisone[ref]Takeda S, Misawa K, Yamamoto I, Watanabe K. Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis. Drug Metab Dispos. 2008;36(9):1917-21.[/ref].

Numerous clinical trials performed by the Center for Medical Cannabis Research in San Diego also confirm the efficacy of cannabis as a therapeutic tool and is effective in providing relief from chronic neuropathic pain due to diabetes and HIV[ref]Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. J Pain. 2015;[/ref]. The diabetes study also showed reductions in pain in a dose dependent fashion while the HIV study showed that smoked cannabis led to significant reductions in pain in comparison to pre-treatment baseline levels.

These are just a few of some of the studies performed that support the use of cannabis for pain relief. There is an overwhelming amount of data acknowledges cannabis as an effective medicine, however until the stigmas surrounding this plant change it will continue to be viewed as inferior.