“Significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur during malignant transformation in various types of cancer, including gliomas. Cannabinoids exert anti-proliferative action in tumor cells. Induction of cell death by cannabinoid treatment…”
Tag Archives: Cannabinoids
Cannabinoids and gliomas.
Abstract
“Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances–the endocannabinoids–that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.”
Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells
“Normal tissue toxicity limits the efficacy of current treatment modalities for glioblastoma multiforme (GBM).
We evaluated the influence of cannabinoids on cell proliferation, death, and morphology of human GBM cell lines and in primary human glial cultures, the normal cells from which GBM tumors arise. The influence of a plant derived cannabinoid agonist, Delta(9)-tetrahydrocannabinol Delta(9)-THC), and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy.
We discovered that Delta(9)-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2. Delta(9)-THC was also more potent at inhibiting the proliferation of GBM cells compared to WIN 55,212-2. The effects of Delta(9)-THC and WIN 55,212-2 on the GBM cells were partially the result of cannabinoid receptor activation.
The same concentration of Delta(9)-THC that significantly inhibits proliferation and increases death of human GBM cells has no significant impact on human primary glial cultures. Evidence of selective efficacy with WIN 55,212-2 was also observed but the selectivity was less profound, and the synthetic agonist produced a greater disruption of normal cell morphology compared to Delta(9)-THC.”
https://www.ncbi.nlm.nih.gov/pubmed/16078104
https://link.springer.com/article/10.1007%2Fs11060-004-5950-2
Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells.
“The active components of Cannabis sativa L., Cannabinoids, traditionally used in the field of cancer for alleviation of pain, nausea, wasting and improvement of well-being have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory activity and induction of tumor regression. Here we used several experimental approaches, which identified delta-9-tetrahydrocannabinol (Delta(9)-THC) as an essential mediator of cannabinoid antitumoral action.”
“CONCLUSIONS:
Delta(9)-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.”
Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas
“Cannabinoids, the active components of Cannabis sativa L. (marijuana), and their derivatives exert a wide array of effects by activating their specific G protein-coupled receptors CB1 and CB2, which are normally engaged by a family of endogenous ligands–the endocannabinoids. Marijuana and its derivatives have been used in medicine for many centuries, and there is currently a renaissance in the study of the therapeutic effects of cannabinoids. Today, cannabinoids are approved to palliate the wasting and emesis associated with cancer and AIDS chemotherapy, and ongoing clinical trials are determining whether cannabinoids are effective agents in the treatment of pain, neurodegenerative disorders such as multiple sclerosis, and traumatic brain injury . In addition, cannabinoid administration to mice and/or rats induces the regression of lung adenocarcinomas, gliomas, thyroid epitheliomas, lymphomas, and skin carcinomas. These studies have also evidenced that cannabinoids display a fair drug safety profile and do not produce the generalized cytotoxic effects of conventional chemotherapies, making them potential antitumoral agents.”
“Gliomas are one of the most malignant forms of cancer, resulting in the death of affected patients within 1–2 two years after diagnosis. Current therapies for glioma treatment are usually ineffective or just palliative. Therefore, it is essential to develop new therapeutic strategies for the management of glioblastoma multiforme, which will most likely require a combination of therapies to obtain significant clinical results. In line with the idea that anti-VEGF treatments constitute one of the most promising antitumoral approaches currently available, the present laboratory and clinical findings provide a novel pharmacological target for cannabinoid-based therapies.”
“The use of cannabinoids in medicine is limited by their psychoactive effects mediated by neuronal CB1 receptors. Although these adverse effects are within the range of those accepted for other medications, especially in cancer treatment, and tend to disappear with tolerance on continuous use, it is obvious that cannabinoid-based therapies devoid of side-effects would be desirable. As glioma cells express functional CB2 receptors, we used a selective CB2 ligand to target the VEGF pathway. Selective CB2 receptor activation in mice also inhibits the growth and angiogenesis of skin carcinomas.”
“Cannabinoids inhibit tumor angiogenesis…”
“Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas”
“Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.”
A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme
“One of the most devastating forms of cancer is glioblastoma multiforme (grade IV astrocytoma), the most frequent class of malignant primary brain tumours. Current standard therapeutic strategies for the treatment of glioblastoma multiforme (surgical resection and focal radiotherapy) are only palliative…”
“The hemp plant Cannabis sativa L. produces approximately 60 unique compounds known as cannabinoids, of which Δ9-tetrahydrocannabinol (THC) is the most important owing to its high potency and abundance in cannabis. Δ9-Tetrahydrocannabinol exerts a wide variety of biological effects by mimicking endogenous substances – the so-called endocannabinoids – that bind to and activate specific cell surface receptors. cannabinoids have been proposed as potential antitumoral agents owing to their ability to inhibit the growth and angiogenesis of various types of tumour xenografts in animal models.”
“Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration… Cannabinoid delivery was safe and could be achieved without overt psychoactive effects…. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.”
Cannabinoids Curb Brain Tumor Growth, First-Ever Patient Trial Shows
“Madrid, Spain: THC administration decreases recurrent glioblastoma multiforme (GBM) tumor growth in humans, according to the findings of the first-ever clinical trial assessing cannabinoids’ anti-tumor action.
Investigators at Complutense University in Spain administered THC intratumorally in nine patients diagnosed with recurrent GBM, an extremely rapid and lethal form of brain tumor. Patients in the study had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumor progression. THC treatment was associated with reduced tumor cell proliferation in two subjects, authors reported.
Investigators did not determine whether THC positively impacted patients’ survival, though they did conclude that cannabinoid therapy does not facilitate cancer growth or decrease patients’ life expectancy. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks, and two patients survived for approximately one year. Survival for GBM patients following diagnosis is typically six to twelve months.
Researchers speculated that newly diagnosed glioma patients may respond more favorably to cannabinoid-based therapies.
Investigators also reported that THC demonstrated significant anti-proliferative activity on human GBM cells in culture.
“The fair safety profile of THC, together with its possible anti-proliferative action on tumor cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids,” investigators concluded.
In 2005, investigators at the California Pacific Medical Center Research Institute in San Francisco reported that THC selectively decreases the proliferation of malignant cells and induces cell death in human GBM cell lines. Healthy cells in the study were unaffected by THC administration.
Separate preclinical studies indicate that cannabinoids and endocannabinoids can stave off tumor progression and trigger cell death in other cancer cell lines, including breast carcinoma, prostate carcinoma, colectoral carcinoma, skin carcinoma, and pancreatic adenocarcinoma.”
http://norml.org/news/2006/07/13/cannabinoids-curb-brain-tumor-growth-first-ever-patient-trial-shows
Cannabinoids As Cancer Hope
by Paul Armentano
Senior Policy Analyst
NORML | NORML Foundation
““Cannabinoids possess … anticancer activity [and may] possibly represent a new class of anti-cancer drugs that retard cancer growth, inhibit angiogenesis (the formation of new blood vessels) and the metastatic spreading of cancer cells.” So concludes a comprehensive review published in the October 2005 issue of the scientific journal Mini-Reviews in Medicinal Chemistry.
Not familiar with the emerging body of research touting cannabis’ ability to stave the spread of certain types of cancers? You’re not alone.
For over 30 years, US politicians and bureaucrats have systematically turned a blind eye to scientific research indicating that marijuana may play a role in cancer prevention — a finding that was first documented in 1974. That year, a research team at the Medical College of Virginia (acting at the behest of the federal government) discovered that cannabis inhibited malignant tumor cell growth in culture and in mice. According to the study’s results, reported nationally in an Aug. 18, 1974, Washington Post newspaper feature, administration of marijuana’s primary cannabinoid THC, “slowed the growth of lung cancers, breast cancers and a virus-induced leukemia in laboratory mice, and prolonged their lives by as much as 36 percent.”
Despite these favorable preclinical findings, US government officials dismissed the study (which was eventually published in the Journal of the National Cancer Institute in 1975), and refused to fund any follow-up research until conducting a similar — though secret — clinical trial in the mid-1990s. That study, conducted by the US National Toxicology Program to the tune of $2 million concluded that mice and rats administered high doses of THC over long periods experienced greater protection against malignant tumors than untreated controls.
Rather than publicize their findings, government researchers once again shelved the results, which only came to light after a draft copy of its findings were leaked in 1997 to a medical journal, which in turn forwarded the story to the national media.
Nevertheless, in the decade since the completion of the National Toxicology trial, the U.S. government has yet to encourage or fund additional, follow up studies examining the cannabinoids’ potential to protect against the spread cancerous tumors.
Fortunately, scientists overseas have generously picked up where US researchers so abruptly left off. In 1998, a research team at Madrid’s Complutense University discovered that THC can selectively induce apoptosis (program cell death) in brain tumor cells without negatively impacting the surrounding healthy cells. Then in 2000, they reported in the journal Nature Medicine that injections of synthetic THC eradicated malignant gliomas (brain tumors) in one-third of treated rats, and prolonged life in another third by six weeks.
In 2003, researchers at the University of Milan in Naples, Italy, reported that non-psychoactive compounds in marijuana inhibited the growth of glioma cells in a dose dependent manner and selectively targeted and killed malignant cancer cells.
The following year, researchers reported in the journal of the American Association for Cancer Research that marijuana’s constituents inhibited the spread of brain cancer in human tumor biopsies. In a related development, a research team from the University of South Florida further noted that THC can also selectively inhibit the activation and replication of gamma herpes viruses. The viruses, which can lie dormant for years within white blood cells before becoming active and spreading to other cells, are thought to increase one’s chances of developing cancers such as Karposis Sarcoma, Burkitts lymphoma, and Hodgkins disease.
More recently, investigators published pre-clinical findings demonstrating that cannabinoids may play a role in inhibiting cell growth of colectoral cancer, skin carcinoma, breast cancer, and prostate cancer, among other conditions. When investigators compared the efficacy of natural cannabinoids to that of a synthetic agonist, THC proved far more beneficial – selectively decreasing the proliferation of malignant cells and inducing apoptosis more rapidly than its synthetic alternative while simultaneously leaving healthy cells unscathed.
Nevertheless, US politicians have been little swayed by these results, and remain steadfastly opposed to the notion of sponsoring – or even acknowledging – this growing body clinical research, preferring instead to promote the unfounded notion that cannabis use causes cancer. Until this bias changes, expect the bulk of research investigating the use of cannabinoids as anticancer agents to remain overseas and, regrettably, overlooked in the public discourse.”
http://norml.org/component/zoo/category/cannabinoids-as-cancer-hope
Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L
“The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Δ9-THC and other cannabinoids… Results of this study show that Δ9-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”
“Cannabis sativa L. is one of the most widely used plants for both recreational and medicinal purposes. To date a total of 525 natural constituents covering several chemical classes have been isolated and identified from C. sativa. The cannabinoids belong to the chemical class of terpenophenolics, of which 85 have been uniquely identified in cannabis, including the most psychoactive cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC). The most common natural plant cannabinoids (phytocannabinoids) are: Δ9-THC, cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN). Several of the identified cannabinoids are both chemically and pharmacologically poorly characterized due to insufficient isolated amounts; however, the pharmacology of Δ9-THC has been widely studied, and it is regarded as the main psychoactive constituent of cannabis.”
“The psychological and physiological effects of cannabis have been extensively characterized, including euphoria, analgesia, sedation, memory and cognitive impairment, appetite stimulation, and anti-emesis. Most of these effects have been primarily attributed to Δ9-THC. Major advances in the field of cannabinoid research were achieved following the unraveling of the molecular mechanism underlying the actions of Δ9-THC and the discovery of the endocannabinoid system. The endocannabinoid system is regarded as a neuromodulator, and is comprised of cannabinoid receptors (primarily CB1 and CB2 receptors), their endogenous ligands, and enzymes responsible for the synthesis and metabolism of these ligands.”
“In addition to the established effects of cannabis, it is well recognized that mood elevation is one of the components of the complex experience elicited by cannabis. Much of our knowledge regarding cannabis effect on mood and anxiety is based on individual reports following cannabis use for medicinal or recreational purposes. Several anecdotal reports describe the antidepressant effect of cannabis, with patients confirming beneficial outcomes from its use in primary or secondary depressive disorders…”
“In conclusion, our results show that phytocannabinoids, including Δ9-THC, CBD, and CBC, exert antidepressant-like actions in animal models of behavioral despair. The exact mechanism underlying such activity is still unclear and confounded by the fact that these compounds have varying binding profiles to the established cannabinoid CB1 as well as to non CB1 receptors. The results support the effect of phytocannabinoids on mood disorders and provide potential leads for further studies.”
Antidepressant-like effects of Δ⁹-tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depression.
Abstract
“The endocannabinoid signalling system is widely accepted to play a role in controlling the affective state. Plant cannabinoids are well known to have behavioural effects in animals and humans and the cannabinoid CB(1) receptor antagonist rimonabant has recently been shown to precipitate depression-like symptoms in clinical trial subjects. The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ⁹-tetrahydrocannabinol (THC) and rimonabant on intact and olfactory bulbectomised (OB) rats used as a model of depression. As expected, OB rats were hyperactive in the open field. Repeated THC (2 mg/kg, i.p. once every 48 h for 21 days) and rimonabant (5 mg/kg, i.p. once every 48 h for 21 days) reduced this hyperactivity, which is typical of clinically effective antidepressant drugs. In intact animals, chronic THC increased brain derived neurotrophic factor (BDNF) expression levels in the hippocampus and frontal cortex but rimonabant had no effect. Rimonabant increased the levels of phosphorylated extracellular signal regulated kinases (p-ERKs(1/2)) in the hippocampus and prefrontal cortex and THC also increased expression in frontal cortex. OB did not affect BDNF or p-ERK(1/2) expression in the hippocampus or frontal cortex and in, contrast to the intact animals, neither THC nor rimonabant altered expression in the OB rats. These findings indicate antidepressant-like behavioural properties of both THC and rimonabant in OB rats although additional studies are required to clarify the relationship between the chronic effects of cannabinoids in other pre-clinical models and in human depression.”