By Narda Robinson, DO, DVM The search for plant-based cancer cures turns up exciting prospects such as curcumin (from the Indian spice turmeric) and medicinal mushrooms from Asia. Scientific research is highlighting myriad mechanisms of each of these promising plants, finding pro-apoptotic, anti-inflammatory and immune-enhancing benefits. Prudent medical and veterinary practice warrants our being able to discuss with our clients the scientific basis of botanical compounds to help them make informed decisions about their own health care and that of their family members. The most recent botanical gaining recognition involves cannabis and its chemical constituents, called cannabinoids.1 In fact, the National Cancer Institute (NCI) website now carries an entire section on cannabis. There, NCI presents information on the potential benefits, such as antiemetic effects, appetite stimulation and the ability to both alleviate pain and improve sleep. The authors also review the antitumor effects of cannabinoids, enumerating studies and mechanisms. Despite the mounting evidence that cannabis derivatives can have anticancer benefits, the question of whether cannabis can “cure” cancer remains unanswered.2 In fact, the more we learn, the more we can see how much we don’t know about cannabinoid chemistry and cancer. The study of delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) is also teaching us that in order to find better answers, we need to ask better questions. The natural tendency to expect to find a simplistic “yes” or “no” answer to whether cannabis fights cancer has to mature into a systematic analysis of which cannabinoids fight which type(s) of cancer—if any—and in which dose administered through which avenue, i.e., oral, intravenous, intratumor, topical or other. We already know that cells throughout the body contain within their membrane a class of receptors known as cannabinoid receptors. These receptors may hold the key to how cannabis “cans” cancer. Until recently, most of the research on cannabinoid receptors focused on two types, CB1 and CB2, but now there are thought to be 13 or more.3 CB1receptors appear throughout the body such as in the brain, adipose tissue, the myocardium, vascular endothelium and sympathetic nerve terminals. CB2 receptors are more discretely located on lymphoid tissue and peripheral macrophages. CB4 has been identified in endothelial linings of blood vessels and CB6 has putative anti-inflammatory properties.4 Three major groups of ligands activate these receptors, including endogenous substances called cannabinoids, plant-based cannabinoids such as those found in marijuana and hemp, and synthetic cannabinoids produced in the laboratory. While THC binds directly to cannabinoid receptors, CBD acts instead as an indirect agonist and modulator of THC activity Over the past decade, investigations of tumor tissue have identified CB1 and CB2 receptors in a wide array of tumor types. Compared to nonmalignant tissue, malignant tumors express a higher number of cannabinoid receptors, though exceptions to this rule exist.5 Moreover, patients with high cannabinoid receptor expression in tumors from pancreatic, prostate and squamous cell carcinoma have a poorer prognosis, whereas those with a high concentration of CB1 and CB2 in hepatocellular carcinoma tumors have a better prognosis.6 Researchers are exploring how, and if, cannabinoids such as THC can kill cancer cells. What they have found thus far is that mechanisms of cannabinoid-induced cancer cell death first involve the binding of cannabinoid agonists to CB1 or CB2. This binding triggers the synthesis of chemicals within the cell that result in its death through autophagy and apoptosis.7 For gliomas specifically, cannabinoids decrease tumor growth by reducing tumor angiogenesis, inhibiting tumor cell invasion, inducing tumor cell differentiation and possibly arresting the cell cycle. In so doing, cannabinoids regulate key cell signaling pathways involved in tumor cell survival.8 What remains to be answered is whether THC, systemically administered, can exhibit curative effects at clinically relevant concentrations and whether it did so with good predictivity. Research has indicated that THC administered directly into tumors in mouse models has reduced their size.9 Intratumoral administration allows for the use of higher concentrations of THC than might be acceptable systemically. One clinical application for which intratumoral THC has attracted attention is glioblastoma multiforme, a condition that is otherwise difficult to treat. As with any botanical compound, learning about the scientifically based mechanisms of action is merely the first step. What we need to know as well are how the products interact with others, pharmaceutical and botanical, along with their purity, potency and proven benefits in target species. When and why might the body begin to exhibit tolerance to cannabinoids, and will the liver begin inducing enzymes to metabolize the compounds?10 Could cannabinoids and conventional chemotherapy work together, even synergistically, so that clinicians could lower the dose of the pharmaceutical and thereby lower the risk of adverse side effects? In human medicine, cannabis has been perceived as highly effective by patients with advanced cancer for pain and symptom management.11 For animals with cancer, more caregivers are asking whether cannabis can help their loved one. What are we going to tell them without more research? References National Cancer Institute. Cannabis and cannabinoids for health professionals (PDQ). Accessed at http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq on 09-20-15. Fowler CJ. Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: a critical examination of the preclinical literature. Clinical Pharmacology & Therapeutics. 2015; 97(6):587-596. Iqbal O. Endocannabinoid system and pathophysiology of adipogenesis: current management of obesity. Personalized Medicine. 2007;4(3):307-319. Iqbal O. Endocannabinoid system and pathophysiology of adipogenesis: current management of obesity. Personalized Medicine. 2007;4(3):307-319. Fowler CJ. Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: a critical examination of the preclinical literature. Clinical Pharmacology & Therapeutics. 2015; 97(6):587-596. Fowler CJ. Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: a critical examination of the preclinical literature. Clinical Pharmacology & Therapeutics. 2015; 97(6):587-596. Abrams DI and Guzman M. Cannabis in cancer care. Clinical Pharmacology and Therapeutics. 2015;97(6):575-586. Chakravarti B, Ravi J, and Ganju RK. Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget. 2015; 5(15):5853-5872. Fowler CJ. Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: a critical examination of the preclinical literature. Clinical Pharmacology & Therapeutics. 2015; 97(6):587-596. Abrams DI and Guzman M. Cannabis in cancer care. Clinical Pharmacology and Therapeutics. 2015; 97(6):575-586. Waissengrin B, Urban D, Leshem Y, et al. Patterns of medical cannabis among Israeli cancer patients: a single institution experience. Journal of Pain and Symptom Management. 2015; 49(2):223-230. Originally published in the November 2015 issue of Veterinary Practice News. Did you enjoy this article? Then subscribe today!
