Cannabis: A Prehistoric Remedy for the Deficits of Existing and Emerging Anticancer Therapies

“Cannabis has been used medicinally for centuries and numerous species of this genus are undoubtedly amongst the primeval plant remedies known to humans.

Cannabis sativa in particular is the most reported species, due to its substantial therapeutic implications that are owed to the presence of chemically and pharmacologically diverse cannabinoids.

These compounds have long been used for the palliative treatment of cancer.

Recent advancements in receptor pharmacology research have led to the identification of cannabinoids as effective antitumor agents.

This property is accredited for their ability to induce apoptosis, suppress proliferative cell signalling pathways and promote cell growth inhibition.

Evolving lines of evidence suggest that cannabinoid analogues, as well as their receptor agonists, may offer a novel strategy to treat various forms of cancer.

This review summarizes the historical perspective of C. sativa, its potential mechanism of action, and pharmacokinetic and pharmacodynamic aspects of cannabinoids, with special emphasis on their anticancer potentials.”

http://www.xiahepublishing.com/ArticleFullText.aspx?sid=2&jid=3&id=10.14218%2FJERP.2017.00012

Cannabis products.

“Cannabis products. First row, left to right: Indian, Lebanese, Turkish and Pakistani hashish. Second row, left to right: Swiss hashish, Zairean marijuana, Swiss marijuana, Moroccan hash oil.”

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Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

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“Anandamide is a lipid neurotransmitter derived from arachidonic acid, a polyunsaturated fatty acid.

The chemical differences between anandamide and arachidonic acid result in a slightly enhanced solubility in water and absence of an ionisable group for the neurotransmitter compared with the fatty acid. In this review, we first analyze the conformational flexibility of anandamide in aqueous and membrane phases. We next study the interaction of the neurotransmitter with membrane lipids and discuss the molecular basis of the unexpected selectivity of anandamide for cholesterol and ceramide from among other membrane lipids.

We show that cholesterol behaves as a binding partner for anandamide, and that following an initial interaction mediated by the establishment of a hydrogen bond, anandamide is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu.

The complex is then directed to the anandamide cannabinoid receptor (CB1) which displays a high affinity binding pocket for anandamide. We propose that cholesterol may regulate the entry and exit of anandamide in and out of CB1 by interacting with low affinity cholesterol recognition sites (CARC and CRAC) located in transmembrane helices.

The mirror topology of cholesterol binding sites in the seventh transmembrane domain is consistent with the delivery, extraction and flip-flop of anandamide through a coordinated cholesterol-dependent mechanism. The binding of anandamide to ceramide illustrates another key function of membrane lipids which may occur independently of protein receptors.

Interestingly, ceramide forms a tight complex with anandamide which blocks the degradation pathway of both lipids and could be exploited for anti-cancer therapies.”

“The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20983/

“The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774787/

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Novel therapeutic applications of cannabinoids in cancer disease

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“The present review shows that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

The endocannabinoid system is an almost ubiquitous signalling system involved in the control of cell fate. Recent studies have investigated the possibility that drugs targeting the endocannabinoid system might be used to retard or block cancer growth.

The endocannabinoids have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell signalling pathways. Therefore, the present review indicated that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

  • Triggering cell death, through a mechanism called apoptosis
  • Stopping cells from dividing
  • Preventing new blood vessels from growing into tumours
  • Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighbouring tissue
  • Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

Furthermore, the novel therapeutic application of cannabinoids in cancer disease, described here, strongly support the idea that cannabinoids may induce benefical effect in cancer treatment.”

http://www.oatext.com/novel-therapeutic-applications-of-cannabinoids-in-cancer-disease.php

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Endocannabinoid system and anticancer properties of cannabinoids

Folia Biologica et Oecologica

“Cannabinoids impact human body by binding to cannabinoids receptors (CB1 and CB2).

The two main phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

THC interacts with CB1 receptors occurring in central nervous system and is responsible for psychoactive properties of marijuana. CBD has low affinity to CB1 receptor, has no psychoactive characteristics and its medical applications can be wider.

CB receptors are part of a complex machinery involved in regulation of many physiological processes – endocannabinoid system.

Cannabinoids have found some applications in palliative medicine, but there are many reports concerning their anticancer affects.

Agonists of CB1 receptors stimulate accumulation of ceramides in cancer cells, stress of endoplasmic reticulum (ER stress) and, in turn, apoptosis. Effects of cannabinoids showing low affinity to CB receptors is mediated probably by induction of reactive oxygen species production.

Knowledge of antitumor activity of cannabinoids is still based only on preclinical studies and there is a necessity to conduct more experiments to assess the real potential of these compounds.”

https://content.sciendo.com/view/journals/fobio/12/1/article-p11.xml

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INSIGHT ON THE IMPACT OF ENDOCANNABINOID SYSTEM IN CANCER: A REVIEW.

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“In the last decades, the endocannabinoid system has attracted a great interest in medicine and cancer disease is probably one of its most promising therapeutic areas.

On the one hand, endocannabinoid system expression has been found altered in numerous types of tumours compared to healthy tissue, and this aberrant expression has been related to cancer prognosis and disease outcome, suggesting a role of this system in tumour growth and progression that depends on cancer type.

On the other hand, it has been reported that cannabinoids exert an anticancer activity by inhibiting the proliferation, migration and/or invasion of cancer cells; and also tumour angiogenesis.

The endocannabinoid system may be considered as a new therapeutic target, although further studies to fully establish the effect of cannabinoids on tumour progression remain necessary.”

https://www.ncbi.nlm.nih.gov/pubmed/29663308

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Cannabis and Anti-Cancer Drugs: Societal Usage and Expected Pharmacological Interactions – A Review.

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“Cannabis is a plant that has been used for centuries to relieve a wide range of symptoms. Since the 1960s, interest in medical research into this plant has grown steadily. Already very popular for recreational use, a growing number of consumers not accustomed to using cannabis for psychoactive purposes, have begun to use it as an alternative or complement to mainstream pharmaceutical medicines. The principal unsubstantiated or “social” uses of cannabis are based mainly on data that is at best controversial, but usually not scientifically proven. The aim of this review is to identify the scientific basis and reasons that lead patients with cancer to consume cannabis, and also to identify whether there is a risk of interaction between cannabis and anti-cancer medicines through drug transporters (P-glycoprotein and other ABC-superfamily members) Cytochromes P450 (3A, 1A, 2B, 2C 2D families…) and glucuronyl-transferases.”

https://www.ncbi.nlm.nih.gov/pubmed/29660159

https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12373

“Cannabinoids as Anticancer Drugs.”  https://www.ncbi.nlm.nih.gov/pubmed/28826542

“Targeting the endocannabinoid system as a potential anticancer approach.”  https://www.ncbi.nlm.nih.gov/pubmed/29390896

“Anticancer mechanisms of cannabinoids”   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/

http://www.thctotalhealthcare.com/tag/anticancer/

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The use of cannabis in supportive care and treatment of brain tumor

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“Anticancer Effects of Cannabinoids may be able to Prolong Life.

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.

THC, a partial CB1, CB2 agonist, has the stigma of psychotropic effects that are mediated by CB1 stimulation. However, CB1 stimulation is necessary for improving mood and appetite and many other effects. At present, it is hard to imagine a better approach than adjusting THC doses individually to balance wanted versus unwanted effects. Generally, higher doses are needed to achieve analgesic and antiemetic effects. Even much higher, supraphysiologic oral doses would be needed to combat tumors.

Combinations were synergistic under many circumstances such as in pain and antitumor studies. Cannabinoids differ in their antitumor activities and probably in their mechanisms and targets, which is a rationale for combinations. However, for many pharmacological effects (except against tumors) roughly 10-times higher daily doses are needed for CBD compared to THC.

In summary, the endocannabinoid system is likely playing a crucial role in palliative care. The future will show whether an optimized treatment strategy with cannabinoids can also prolong life of brain tumor patients by their virtue to combat cancer cells.”

https://academic.oup.com/nop/article/4/3/151/2918616

“Cannabinoid Drug Prolongs the Life of Brain Tumor Patients in Phase II Trials”  https://labiotech.eu/gw-pharmaceuticals-brain-tumor/

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Medical cannabis in the treatment of cancer pain and spastic conditions and options of drug delivery in clinical practice.

“The use of cannabis for medical purposes has been recently legalised in many countries including the Czech Republic. As a result, there is increased interest on the part of physicians and patients in many aspects of its application. This mini review briefly covers the main active substances of the cannabis plant and mechanisms of action. It focuses on two conditions, cancer pain and spasticity in multiple sclerosis, where its effects are well-documented. A comprehensive overview of a few cannabis-based products and the basic pharmacokinetics of marijuana’s constituents follows. The review concludes with an outline for preparing cannabis (dried inflorescence) containing drug dosage forms that can be produced in a hospital pharmacy.”

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Cannabis sativa Extract Reduces Cytoskeletal Associated Proteins in Breast Cancer Cell Line

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Study shows non-hallucinogenic cannabinoids are effective anti-cancer drugs

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“New research has shown that the non-hallucinogenic components of cannabis could act as effective anti-cancer agents. The anti-cancer properties of tetrahydrocannabinol (THC), the primary hallucinogenic component of cannabis, has been recognised for many years, but research into similar cannabis-derived compounds, known as cannabinoids, has been limited.

The study was carried out by a team at St George’s, University of London. It has been published in the journal Anticancer Research. The team, led by Dr Wai Liu and colleagues carried out laboratory investigations using a number of cannabinoids, either alone or in combination with each other, to measure their anti-cancer actions in relation to leukaemia.

Of six cannabinoids studied, each demonstrated anti-cancer properties as effective as those seen in THC. Importantly, they had an increased effect on cancer cells when combined with each other.

Dr Liu said: “This study is a critical step in unpicking the mysteries of cannabis as a source of medicine. The cannabinoids examined have minimal, if any, hallucinogenic side effects, and their properties as anti-cancer agents are promising.

“These agents are able to interfere with the development of cancerous cells, stopping them in their tracks and preventing them from growing. In some cases, by using specific dosage patterns, they can destroy cancer cells on their own.

“Used in combination with existing treatment, we could discover some highly effective strategies for tackling cancer. Significantly, these compounds are inexpensive to produce and making better use of their unique properties could result in much more cost effective anti-cancer drugs in future.”

The study examined two forms of cannabidiol (CBD), two forms of cannabigerol (CBG) and two forms of cannabigevarin (CBGV). These represent the most common cannabinoids found in the cannabis plant apart from THC.” https://www.sgul.ac.uk/alumni/magazine/study-shows-non-hallucinogenic-cannabinoids-are-effective-anti-cancer-drugs

“Enhancing the Activity of Cannabidiol and Other Cannabinoids In Vitro Through Modifications to Drug Combinations and Treatment Schedules”  http://ar.iiarjournals.org/content/33/10/4373.abstract

“Non-hallucinogenic cannabinoids are effective anti-cancer drugs” https://www.sciencedaily.com/releases/2013/10/131014094105.htm

“Cannabinoids used in sequence with chemotherapy are a more effective treatment for cancer. New research has confirmed that cannabinoids – the active chemicals in cannabis – are effective in killing leukaemia cells, particularly when used in combination with chemotherapy treatments.” https://www.sgul.ac.uk/news/news-archive/cannabinoids-used-in-sequence-with-chemotherapy-are-a-more-effective-treatment-for-cancer
 
“Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration.” https://www.ncbi.nlm.nih.gov/pubmed/28560402
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