Oncology

Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC. Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive. Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further. Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today’s scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.

Cannabidiol (CBD), the major non-psychoactive compound found in cannabis, is frequently used both as a nutraceutical and therapeutic. Despite anecdotal evidence as an anticancer agent, little is known about the effect CBD has on cancer cells. Given the intractability and poor prognoses of brain cancers in human and veterinary medicine, we sought to characterize the in vitro cytotoxicity of CBD on human and canine gliomas. Glioma cells treated with CBD showed a range of cytotoxicity from 4.9 to 8.2 μg/ml; canine cells appeared to be more sensitive than human. Treatment with >5 μg/ml CBD invariably produced large cytosolic vesicles. The mode of cell death was then interrogated using pharmacologic inhibitors. Inhibition of apoptosis was sufficient to rescue CBD-mediated cytotoxicity. Inhibition of RIPK3, a classical necroptosis kinase, also rescued cells from death and prevented the formation of the large cytosolic vesicles. Next, cellular mitochondrial activity in the presence of CBD was assessed and within 2 hours of treatment CBD reduced oxygen consumption in a dose dependent manner with almost complete ablation of activity at 10 μg/ml CBD. Fluorescent imaging with a mitochondrial-specific dye revealed that the large cytosolic vesicles were, in fact, swollen mitochondria. Lastly, calcium channels were pharmacologically inhibited and the effect on cell death was determined. Inhibition of mitochondrial channel VDAC1, but not the TRPV1 channel, rescued cells from CBD-mediated cytotoxicity. These results demonstrate the cytotoxic nature of CBD in human and canine glioma cells and suggest a mechanism of action involving dysregulation of calcium homeostasis and mitochondrial activity.

Vascular endothelial growth factor (VEGF) is a key regulator in both physiologic and pathologic angiogenesis, and cannabinoids decrease VEGF release in human and murine cancer cells. The aim of this study was to assess the in vitro effects of a synthetic cannabinoid, WIN-55,212-2, on the expression of the proangiogenic factor VEGF-A in the canine osteosarcoma cell line 8. After analysis of gene expression by quantitative real-time polymerase chain reaction, the compound decreased VEGF-A expression by 35% ± 10% (P < 0.0001) as compared with the control. This synthetic cannabinoid shows promise as a potential inhibitor of angiogenesis, and further studies are warranted to investigate its in vivo effects and to explore the potential of this and related compounds as adjuvant cancer therapy in the dog.

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.

Background: Cannabis for cancer is very topical and, given the use of illicit cannabis preparations used in this vulnerable population, research investigating standardised, quality-assured medicinal cannabis is critical to inform clinicians and assist patient safety. Methods: A randomized trial involving adult patients diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction were eligible for inclusion in a tolerability study on two different ratios of medicinal cannabis. Baseline screening of brain morphology, blood pathology, functional status, and cognition was conducted. A retrospective control group was used for comparison for secondary outcomes. Results: Participants (n=88) were on average 53.3 years old. A paired t-test assessed the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) between groups from baseline to week 12 found that the 1:1 ratio favoured both physical (p=0.025) and functional (p=0.014) capacity and improved sleep (p=0.009). Analysis of changes from baseline to week 12 also found 11% of 61 participants had a reduction in disease, 34% were stable, 16% had slight enhancement, and 10% had progressive disease. No serious adverse events occurred. Side effects included dry mouth, tiredness at night, dizziness, drowsiness. Conclusion: This study demonstrated that a single nightly dose of THC-containing medicinal cannabis was safe, had no serious adverse effects and was well tolerated in patients. Medicinal cannabis significantly improved sleep, functional wellbeing, and quality of life.

Background Canine urothelial carcinoma is the most common form of canine bladder cancer. Treatment with chemotherapy has variable response rates leading to most dogs succumbing to their disease within a year. Cannabidiol is an emerging treatment within the field of oncology. In reported in vivo studies, cannabidiol has induced apoptosis, reduced cell migration, and acted as a chemotherapy sensitizer in various human tumor types. The aim of this study was to characterize the effects of cannabidiol on canine urothelial carcinoma cell viability and apoptosis as both a single agent and in combination with chemotherapy in vitro. Results Cannabidiol reduced cell viability and induced apoptosis in canine urothelial cells as determined by crystal violet viability assay and annexin V/propidium iodide flow cytometry. Furthermore, combinations of cannabidiol with mitoxantrone and vinblastine chemotherapy yielded significantly reduced cell viability and increased apoptosis compared to single agent treatment alone. The drug interactions were deemed synergistic based on combination index calculations. Conversely, the combination of cannabidiol and carboplatin did not result in decreased cell viability and increased apoptosis compared to single agent treatment. Combination index calculations suggested an antagonistic interaction between these drugs. Finally, the combination of the non-steroidal anti-inflammatory drug piroxicam with cannabidiol did not significantly affect cell viability, although, some cell lines demonstrated decreased cell viability when mitoxantrone was combined with piroxicam. Conclusions Cannabidiol showed promising results as a single agent or in combination with mitoxantrone and vinblastine for treatment of canine urothelial carcinoma cells. Further studies are justified to investigate whether these results are translatable in vivo.

Low tetrahydrocannabinol Cannabis sativa products, also known as hemp products, have become widely available and their use in veterinary patients has become increasingly popular. Despite prevalence of use, the veterinary literature is lacking and evidence-based resource for cannabinoid efficacy. The most prevailing cannabinoid found in hemp is cannabidiolic acid (CBDA) and becomes cannabidiol (CBD) during heat extraction; CBD has been studied for its direct anti-neoplastic properties alone and in combination with standard cancer therapies, yielding encouraging results. The objectives of our study were to explore the anti-proliferative and cell death response associated with in vitro treatment of canine cancer cell lines with CBD alone and combination with common chemotherapeutics, as well as investigation into major proliferative pathways (eg, p38, JNK, AKT and mTOR) potentially involved in the response to treatment with CBD. CBD significantly reduced canine cancer cell proliferation far better than CBDA across five canine neoplastic cell lines when treated with concentrations ranging from 2.5 to 10 μg/mL. Combinatory treatment with CBD and vincristine reduced cell proliferation in a synergistic or additive manner at anti-proliferative concentrations with less clear results using doxorubicin in combination with CBD. The cellular signalling effects of CBD treatment, showed that autophagy supervened induction of apoptosis and may be related to prompt induction of ERK and JNK phosphorylation prior to autophagy. In conclusion, CBD is effective at hindering cell proliferation and induction of autophagy and apoptosis rapidly across neoplastic cell lines and further clinical trials are needed to understand its efficacy and interactions with traditional chemotherapy.

Cannabinoids, active components of the plant Cannabis sativa, had been used for centuries in ancient medicine as therapeutic remedies for a variety of conditions, before becoming stigmatized due to their psychoactive effects