The effect of cannabidiol on canine neoplastic cell proliferation and MAP Kinase activation during autophagy and apoptosis

“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 (e.g. p38, JNK, AKT, mTOR) potentially involved in the response to treatment with CBD.

CBD significantly reduced canine cancer cell proliferation far better than cannabidiolic acid (CBDA) across five canine neoplastic cell lines when treated with concentrations ranging from 2.5-10 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 signaling 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.”

https://pubmed.ncbi.nlm.nih.gov/33247539/

https://onlinelibrary.wiley.com/doi/10.1111/vco.12669

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Striking lung cancer response to self-administration of cannabidiol: A case report and literature review.

SAGE Journals

“In spite of new drugs, lung cancer is associated with a very poor prognosis. While targeted therapies are improving outcomes, it is not uncommon for many patients to have only a partial response, and relapse during follow-up. Thus, new drugs or re-evaluation of existing therapies used to treat other non-malignant diseases (drug repurposing) are still needed. While this research both in vitroand in vivo is being carried out, it is important to be attentive to patients where the disease responds to treatments not considered standard in clinical practice.

We report here a patient with adenocarcinoma of the lung who, after declining chemotherapy and radiotherapy, presented with tumour response following self-administration of cannabidiol, a non-psychoactive compound present in Cannabis sativa. Prior work has shown that cannabidiol may have anti-neoplastic properties and enhance the immune response to cancer.

The data presented here indicate that cannabidiol might have led to a striking response in a patient with lung cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/30815264

https://journals.sagepub.com/doi/10.1177/2050313X19832160

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Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs

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“Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. Despite aggressive therapeutic approaches consisting of maximum safe surgical resection and radio-chemotherapy, more than 95% of GBM patients die within 5 years after diagnosis. Thus, there is still an urgent need to develop novel therapeutic strategies against this disease.

Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM.

This review article summarizes the latest findings on the molecular effects of cannabinoids on GBM, both in vitro and in (pre-) clinical studies in animal models and patients.

The therapeutic effect of cannabinoids is based on reduction of tumor growth via inhibition of tumor proliferation and angiogenesis but also via induction of tumor cell death. Additionally, cannabinoids were shown to inhibit the invasiveness and the stem cell-like properties of GBM tumors. Recent phase II clinical trials indicated positive results regarding the survival of GBM patients upon cannabinoid treatment.

Apart from a direct killing effect on tumor cells, cannabinoids can also induce cell cycle arrest thereby inhibiting tumor cell proliferation.

In conclusion, cannabinoids show promising anti-neoplastic functions in GBM by targeting multiple cancer hallmarks such as resistance to programmed cell death, neoangiogenesis, tissue invasion or stem cell-induced replicative immortality.

The effects of cannabinoids can be potentially enhanced by combination of different cannabinoids with each other or with chemotherapeutic agents. This requires, however, a detailed understanding of cannabinoid-induced molecular mechanisms and pharmacological effects.

Ultimately, these findings might foster the development of improved therapeutic strategies against GBM and, perhaps, other diseases of the nervous system as well.”

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00159/full

“Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM.”  https://www.ncbi.nlm.nih.gov/pubmed/29867351

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Cannabis Use in Palliative Oncology: A Review of the Evidence for Popular Indications.

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“A flowering plant of variegated ingredients and psychoactive qualities, cannabis has long been used for medicinal and recreational purposes. Currently, cannabis is approved in several countries for indications of symptomatic alleviation. However, limited knowledge on the benefits and risks precludes inclusion of cannabis in standard treatment guidelines. This review provides a summary of the available literature on the use of cannabis and cannabinoid-based medicines in palliative oncology. Favorable outcomes are demonstrated for chemotherapy-induced nausea and vomiting and cancer-related pain, with evidence of advantageous neurological interactions. Benefit in the treatment of anorexia, insomnia and anxiety is also suggested. Short- and long-term side effects appear to be manageable and to subside after discontinuation of the drug. Finally, cannabinoids have shown anti-neoplastic effects in preclinical studies in a wide range of cancer cells and some animal models. Further research is needed before cannabis can become a part of evidence-based oncology practice.”

https://www.ncbi.nlm.nih.gov/pubmed/28457056

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Quantitative analyses of synergistic responses between cannabidiol and DNA-damaging agents on the proliferation and viability of glioblastoma and neural progenitor cells in culture.

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“Evidence suggests that the non-psychotropic cannabis-derived compound, cannabidiol (CBD), has anti-neoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM).

DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM.

Here we studied the anti-proliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures.

This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system (CNS) toxicity.

We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells.

Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells.

Co-treatment regiments combining CBD and DNA-damaging agents produced synergistic anti-proliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs.

Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells.

Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little-to-no therapeutic window when considering NPCs.”

https://www.ncbi.nlm.nih.gov/pubmed/27821713

“Definition of antineoplastic: inhibiting or preventing the growth and spread of tumors or malignant cells”  http://www.merriam-webster.com/dictionary/antineoplastic

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Comparing the effects of endogenous and synthetic cannabinoid receptor agonists on survival of gastric cancer cells.

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“Anti-neoplastic activity induced by cannabinoids has been extensively documented for a number of cancer cell types; however, this topic has been explored in gastric cancer cells only in a limited number of approaches.

SIGNIFICANCE:

Through a comparative approach, our results support and confirm the therapeutic potential that cannabinoid receptor agonists exert in gastric cancer cells and open possibilities to use cannabinoids as part of a new gastric cancer therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/27640887

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The G1359A-CNR1 gene polymorphism is associated to glioma in Spanish patients.

“The cannabinoid receptor gene 1 (CNR1) encodes the human cannabinoid receptor CB1.

This receptor has a widespread distribution in the central nervous system (CNS), the main ligands being anandamide, 2-araquidonoil glycerol and marijuana constituents.

There is evidence to suggest an anti-neoplastic effect of these ligands in glial tissues mediated through stimulation of the receptor.

Our results suggest that allele G of the CNR1 gene could be associated with a lower susceptibility to glioma.”

http://www.ncbi.nlm.nih.gov/pubmed/21156413

“A glioma is a primary brain tumor that originates from the supportive cells of the brain, called glial cells.” http://neurosurgery.ucla.edu/body.cfm?id=159

“Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death.” http://www.ncbi.nlm.nih.gov/pubmed/15275820

“Cannabinoids, the active components of Cannabis sativa…”  http://www.ncbi.nlm.nih.gov/pubmed/17952650

http://www.thctotalhealthcare.com/category/gllomas/

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Medical Marijuana Is Safe for Children

“Numerous cases show clinical cannabis is effective on illnesses in children”

By  William Courtney, M.D. is CEO of Cannabis International.

“The courage and fortitude of parents who have chosen cannabis compounds to treat their children facing life-threatening illness have raised eyebrows. Some live in terror that their government will take their child away, since medical marijuana is only legal in some states. However, there are numerous cases demonstrating the benefits of clinical cannabis, which happen to threaten a very profitable healthcare industry that relies on conventional drugs, as well as political agendas.

The cannabinoid acids in cannabis have been found to have anti-proliferative, anti-neoplastic, anti-inflammatory, anti-epileptic, anti-ischemic, anti-diabetic, anti-psychotic, anti-nausea, anti-spasmodic, antibiotic, anti-anxiety, and anti-depressant functions. The anti-neoplastic action of cannabis—inhibiting development of malignant cells—was recognized in the 1970s and patented by the U.S. Department of Health and Human Services in 2003.

Out of 7,000 patients, my youngest, an 8-month-old, was diagnosed with a massive midbrain tumor. Pediatric oncologists recommended chemotherapy and radiation. Instead, the parents applied a cannabinoid concentrate to their son’s pacifier twice a day, which resulted in a significant reduction in the size of the tumor in 30 days. The response prevented a million-dollar chemo-radiation hospitalization. The child’s oncologist calls the infant a ‘miracle baby,’ but most medical experts would discount the case as anecdotal, unacceptable in a peer-reviewed journal. But the real peers are other parents reluctant to consent to the devastation of surgery, chemotherapy, and radiation—not those benefiting from the $2.6 trillion healthcare industry.

A 2-year-old spent a year in a pediatric oncology ward, endured 39 hours of brain surgery, received chemotherapy, a bone marrow transplant, and radiation under general anesthesia for 42 days, only to be discharged home on hospice and morphine. The child’s local pediatrician started to treat her with juiced raw cannabis leaf. Two years later, she is still alive, now free of cancer and scar tissue.

A 6-year-old patient with a severe, intractable form of childhood epilepsy, was tried on 11 anti-epileptics, including experimental European drugs. He was finally placed on a drug commonly used to prevent seizures, but continued having 300-400 seizures a day. An ointment produced from cannabis with an increased amount of cannabidiol, a compound patented by HHS, has reduced his seizures to one every 3-4 days.

Several years ago, I proposed that cannabis be recognized as an essential nutrient in the diet of individuals in their 30s and older. Children were excluded out of fear of backlash but it is now my incontrovertible opinion that the immune system of the 8-month-old would never have allowed the tumor to gain a foothold if supported with dietary cannabis, or Vitamin F.

We know Vitamin C deficiency results in scurvy and Vitamin D deficiency results in rickets. Vitamin F, the previous label for Omega-3 and -6 essential fatty acids, is an appropriate appellation for the cannabinoid acids found in cannabis. Vitamin F deficiency allows the cell proliferation found in tumors and cancer. Three studies of over 24,000 children have shown no adverse effects from use of cannabis in pregnancy.

There is no other area in medicine where the heavy hand of federal funding and political agenda compromise valid and reproducible findings to this extent. To advance disease prevention and benign therapy, we must re-examine our preconceptions.”

http://www.usnews.com/opinion/articles/2013/01/07/medical-marijuana-is-safe-for-children

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