Cannabis and Cancer
This is more than just a theory or hypothesis. There is an insurmountable pile of evidence that cannabis cures or treats cancer (and a multitude of other illnesses) in a large amount of cases, and may even prevent it from coming back. The amount of evidence is daunting, and the science is sound.
It is through the encocannabinoid system that cannabis is able to perform its magic. Cannabis has the ability to treat and/or cure a constantly growing list of illnesses, including cancer. Dependent on the individual and the type of cannabinoid used, most types of cancer have been observed responding positively to the introduction of cannabis in the system, including cancer found in the breast, prostate, lung, thyroid, colon, skin, pituitary gland, ovary, pancreas, as well as melanoma, leukemia and more! The cannabinoids in cannabis act through the body’s natural endocannabinoid system to cure and/or treat cancer in several ways.
The most prominent and well researched being:
Antiproliferative Effects of Cannabis: Prevents cancer cells from reproducing, which is fundamentally the biggest issue with cancer cells.
Antiangiogenic Effects of Cannabis: Prevents the formation of new blood vessels needed by tumors to grow; tumors can no longer be supported. (Click for further reading on other foods that contain highly antiangiogenic properties).
Antimetastatic Effects of Cannabis: Prevents cancer from spreading to other organs, acting as a biological shield.
Apoptotic Effects of Cannabis: Seeks out and induces cancerous cells to kill themselves: cancer cells die, healthy cells live. In fact, the healthy cells are specifically protected by cannabinoids like THC.
“Cannabis
use for medicinal purposes
dates back at least 3,000 years.[1-5]
It was introduced into Western
medicine in 1839 by W.B. O’Shaughnessy, a surgeon
who learned of its medicinal properties while working in India for the British
East India Company. Its use was promoted for reported analgesic,
sedative,
anti-inflammatory,
antispasmodic, and anticonvulsant
effects."
Article taken from Cancer.gov
for more info go to https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/_5
ProjectCBD.org Reports the Benefits of Using a Cannabis Therapy for Cancer
“Marijuana Fights Cancer and Helps Manage Side Effects
Researchers Find mounting evidence shows ‘cannabinoids’ in marijuana slow cancer growth, inhibit formation of new blood cells that feed a tumor, and help manage pain, fatigue, nausea, and other side effects.
Researchers Find mounting evidence shows ‘cannabinoids’ in marijuana slow cancer growth, inhibit formation of new blood cells that feed a tumor, and help manage pain, fatigue, nausea, and other side effects.
Cristina Sanchez, a
young biologist at Complutense University in Madrid, was studying cell
metabolism when she noticed something peculiar. She had been screening brain
cancer cells because they grow faster than normal cell lines and thus are
useful for research purposes. But the cancer cells died each time they were
exposed to tetrahydrocannabinol (THC), the principal psychoactive ingredient
of marijuana.
Instead of gaining
insight into how cells function, Sanchez had stumbled upon the anti-cancer
properties of THC. In 1998, she reported in
a European biochemistry journal that THC “induces apoptosis [cell death] in C6
glioma cells,” an aggressive form of brain cancer.
Subsequent
peer-reviewed studies in several countries would show that THC and other
marijuana-derived compounds, known as “cannabinoids,” are effective not
only for cancer-symptom management (nausea, pain, loss of appetite, fatigue),
they also confer a direct antitumoral effect.
A team of Spanish
scientists led by Manuel Guzman conducted the first clinical trial assessing
the antitumoral action of THC on human beings. Guzman administered pure THC via
a catheter into the tumors of nine hospitalized patients with glioblastoma, who
had failed to respond to standard brain-cancer therapies. The results were
published in 2006 in the British Journal of Pharmacology: THC treatment
was associated with significantly reduced tumor cell proliferation in every test subject.
Around the same
time, Harvard University scientists reported that THC slows tumor growth in common lung cancer
and “significantly reduces the ability of the cancer to spread.” What’s more,
like a heat-seeking missile, THC selectively targets and destroys tumor cells
while leaving healthy cells unscathed. Conventional chemotherapy drugs, by
contrast, are highly toxic; they indiscriminately damage the brain
and body.
There is mounting
evidence, according to a report in Mini-Reviews in Medicinal Chemistry,
that cannabinoids “represent a new class of anticancer drugs that retard cancer growth, inhibit
angiogenesis [the formation of new blood cells that feed a tumor] and the
metastatic spreading of cancer cells.”
Dr. Sean McAllister,
a scientist at the Pacific Medical Center in San Francisco, has been studying
cannabinoid compounds for 10 years in a quest to develop new therapeutic
interventions for various cancers. Backed by grants from the National Institute
of Health (and with a license from the DEA), McAllister discovered
that cannabidiol (CBD), a nonpsychoactive component of the marijuana plant, is
a potent inhibitor of breast cancer cell proliferation, metastasis, and
tumor growth.
In 2007, McAllister
published a detailed account of how cannabidiol kills breast cancer
cells and destroys malignant tumors by switching off expression of the ID-1
gene, a protein that appears to play a major role as a cancer cell conductor.”
Article taken from
ProjectCBD.org https://www.projectcbd.org/about/laboratorypreclinical-studies/cbd-thc-and-cancer
What does the American Cancer Society say about the use of marijuana in people with cancer?
“The American Cancer
Society supports the need for more scientific research on cannabinoids for
cancer patients, and recognizes the need for better and more effective
therapies that can overcome the often debilitating side effects of cancer and
its treatment. The Society also believes that the classification of marijuana
as a Schedule I controlled substance by the US Drug Enforcement Administration
imposes numerous conditions on researchers and deters scientific study of
cannabinoids. Federal officials should examine options consistent with federal
law for enabling more scientific study on marijuana.
Medical decisions
about pain and symptom management should be made between the patient and his or
her doctor, balancing evidence of benefit and harm to the patient, the
patient’s preferences and values, and any laws and regulations that may apply.
The American Cancer
Society Cancer Action Network (ACS CAN), the Society’s advocacy affiliate, has
not taken a position on legalization of marijuana for medical purposes because
of the need for more scientific research on marijuana’s potential benefits and
harms. However, ACS CAN opposes the smoking or vaping of marijuana and other
cannabinoids in public places because the carcinogens in marijuana smoke pose
numerous health hazards to the patient and others in the patient’s presence.”
This article was
taken from Cancer.org https://www.cancer.org/treatment/treatments-and-side-effects/complementary-and-alternative-medicine/marijuana-and-cancer.html
The Science behind Cannabis and Cancer
“Can cannabinoids
treat cancer?
There is no doubt
that cannabinoids – both natural and synthetic – are interesting biological
molecules. Hundreds of scientists around the world are investigating their
potential in cancer and other diseases – as well as the harms they can cause –
brought together under the blanket organisation The International
Cannabinoid Research Society.
Researchers first
looked at the anticancer properties of cannabinoids back in the 1970s, andmany hundreds of scientific
papers looking at cannabinoids and cancer have been published since
then. This Wellcome Witness
seminar is also fascinating reading for aficionados of the history of
medical cannabis, including the scientific, political and legal twists. [Updated
KA 26/03/14]
Lab research
Virtually all the
scientific research investigating whether cannabinoids can treat cancer has
been done using cancer cells grown in the lab or animal models. It’s important
to be cautious when extrapolating these results up to real live patients, who
tend to be a lot more complex than a Petri dish or a mouse.
Virtually all the
research into cannabinoids and cancer so far has been done in the lab.
Through many
detailed experiments, handily summarised in this recent article in the
journal Nature Reviews Cancer,
scientists have discovered that various cannabinoids (both natural and
synthetic) have a wide range of effects in the lab, including:
- 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
All these effects
are thought to be caused by cannabinoids locking onto the CB1 and CB2
cannabinoid receptors. It also looks like cannabinoids can exert effects on
cancer cells that don’t involve cannabinoid receptors, although it isn’t yet
clear exactly what’s going on there.
So far, the best
results in the lab or animal models have come from using a combination of
highly purified THC and cannabidiol (CBD), a cannabinoid
found in cannabis plants that counteracts the psychoactive effects of THC. But
researchers have also found positive results using synthetic cannabinoids, such
as a molecule called JWH-133.
It’s not all good
news though, as there’s also evidence that cannabinoids may also have
undesirable effects on cancer.
For example, some
researchers have found that although high doses of THC can kill cancer cells,
they also harm crucial blood vessel cells,
although this may help their anti-cancer effect by preventing blood vessels
growing into a tumour. And under some circumstances, cannabinoids can
actually encourage cancer cells to grow, or
have different effects depending on the dosage and levels of cannabinoid
receptors present on the cancer cells. [Edited for clarity and to
add reference - KA 27/07/12]
Others have discovered that activating CB2
receptors may actually interfere with the ability of the immune system to
recognise and destroy tumour cells, although some scientists have found that certain
synthetic cannabinoids may enhance immune defences against cancer.
Furthermore, cancer
cells can develop resistance to
cannabinoids and start growing again, although this can be got round by
blocking a certain molecular pathway in the cells known as ALK.
Combining
cannabinoids with other chemotherapy drugs may be a much more effective
approach
And yet more
research suggests that combining cannabinoids with other chemotherapy
drugs may be a much more effective approach. This idea is supported by lab
experiments combining cannabinoids with other drugs including gemcitabine andtemozolomide.”
Article taken from
IFLSCIENCE!
Cannabis Believers Share Their Stories On YouTube
I have come across
some uploaded videos to YouTube that shows supporting evidence in the
beneficial compounds in cannabinoids to help fight cancer. Listen to these
amazing people and their stories about fighting and overcoming cancer.
WATCH as compound in Cannabis oil (THC) kills cancer
cells while leaving healthy cells alone: Lincoln Horsley
Could cannabis oil cure cancer? BBC News: BBC News
Cannabis Cured My Cancer: Aaron Stone
How Cannabinoids Cause Cancer Cells to Die: vito tums
You can’t write a
blog about cannabis and cancer without mentioning Rick Simpson and Rick Simpson
Oil (RSO). He is a very well known cannabis enthusiast who cured himself and supported
the healing benefits of cannabis and shared his special oil with all his
friends and family.
The Rick Simpson Story: Healing Cancer with Cannabis
(more at cureyourowncancer.org):
Lincoln Horsley
Cannabis oil and 4 stage primary liver cancer: Beate Moore
Mike Cutler beats liver cancer with cannabis oil:
#illegallyhealed Podcast with Kevin Quinn
Girl, 7, uses medical marijuana for cancer treatment: CNN
Emily Sander - Lymphoma
Cancer Survivor – Medical Marijuana Treatment: Medical Marijuana 411
Cancer Patient Speaks Out About Medical Marijuana: acluvision
Can Marijuana Help Chemotherapy? Marijuana: Howcast
Melissa Etheridge: Medical marijuana helped restore my
health: hampapartiet
HOW and WHY does Cannabis Cure Cancer – Scientific
Explanation: ShortCannabisVideos
Doctor’s son using Weed for brain Cancer: CannabisCorporation
Tommy Chong Treating Cancer with Cannabis: illegallyhealed
Cannabis Oil Cures Cancer – Lincoln Horsley’s Story: Lincoln Horsley
Even pets with cancer may benefit from Cannabis Oil
Pit Bull Beats Cannabis Oil 8-15
Obviously, cannabis
is not the only cure for cancer. The disease can come from many forms and be
cured by many forms. I found a few videos worth looking into!
Stage-4 Cancer Cured in 7 Weeks without Chemo: Jonathan Landsman with Holistic Oral Health
Summit
Debbie Story: Stage 4 Lung Cancer: sanoviv
She Cured Her Breast Cancer – Here’s How!: iHealthTube.com
Ovarian Cancer and medical marijuana
Non-stop research just keeps pouring in about
the benefits of using cannabis to help with cancer. Here are some published
articles from astounding scientific research. The following articles were found
through ProjectCBD.org. Links to these articles are below under “Resources”.
Marijuana Fights Cancer and Helps Manage Side Effects, Researchers Find
Mounting evidence
shows ‘cannabinoids’ in marijuana slow cancer growth and inhibit formation of
new blood cells that feed a tumor. By Martin A. Lee.
Cristina Sanchez, a
young biologist at Complutense University in Madrid, was studying cell
metabolism when she noticed something peculiar. She had been screening brain cancer cells because they grow faster than normal
cell lines and thus are useful for research purposes. But the cancer cells died each time they were exposed to tetrahydrocannabinol (THC),
the principal psychoactive ingredient of marijuana.
Instead of gaining
insight into how cells function, Sanchez had stumbled upon the anti-cancer
properties of THC. In 1998, she reported in a European
biochemistry journal that THC “induces apoptosis [cell death] in C6 glioma
cells,” an aggressive form of brain cancer.
A team of Spanish
scientists led by Manuel Guzman conducted the first clinical trial assessing
the antitumoral action of THC on human beings. Guzman administered pure THC via
a catheter into the tumors of nine hospitalized patients with glioblastoma, who
had failed to respond to standard brain-cancer therapies. The results were
published in 2006 in the British Journal of Pharmacology: THC treatment
was associated with significantly reduced tumor cell proliferation in every test subject.
Around the same
time, Harvard University scientists reported that THC slows tumor growth in common lung cancer and “significantly
reduces the ability of the cancer to spread.” What’s more, like a heat-seeking
missile, THC selectively targets and destroys tumor cells while leaving healthy
cells unscathed. Conventional chemotherapy drugs, by contrast, are highly
toxic; they indiscriminately damage the brain and body.
Dr. Sean McAllister,
a scientist at the Pacific Medical Center in San Francisco, has been studying
cannabinoid compounds for 10 years in a quest to develop new therapeutic
interventions for various cancers. Backed by grants from the National Institute
of Health (and with a license from the DEA), McAllister discovered that
cannabidiol (CBD), a nonpsychoactive component of the marijuana plant, is a
potent inhibitor of breast cancer cell proliferation, metastasis, and tumor growth.
In 2007, McAllister
published a detailed account of how cannabidiol kills breast cancer cells
and destroys malignant tumors by switching off expression of the ID-1 gene, a
protein that appears to play a major role as a cancer cell conductor.
“Cannabidiol offers
hope of a non-toxic therapy that could treat aggressive forms of cancer without
any of the painful side effects of chemotherapy,” says McAllister, who is
seeking support to conduct clinical trials with the marijuana compound on breast cancer patients.
McAllister’s lab
also is analyzing how CBD works in combination with first-line chemotherapy
agents. His research shows that cannabidiol, a potent antitumoral compound in
its own right, acts synergistically with various anti-cancer pharmaceuticals,
enhancing their impact while cutting the toxic dosage necessary for maximum
effect.
Italian
investigators described CBD as “the most efficacious inducer of apoptosis” in
prostate cancer. Ditto for cannabidiol and colon cancer, according to British
researchers at Lancaster University.
https://www.thedailybeast.com/marijuana-fights-cancer-and-helps-manage-side-effects-researchers-find
Non-stop Published Articles by Various Scientific Researchers Working with Cannabis and Cancer
Cannabidiol as potential anticancer drug.
Over the past years, several lines of evidence support an
antitumourigenic effect of cannabinoids including Δ(9)-tetrahydrocannabinol
(Δ(9)-THC), synthetic agonists, endocannabinoids and endocannabinoid transport
or degradation inhibitors. Indeed, cannabinoids possess anti-proliferative and
pro-apoptotic effects and they are known to interfere with tumour
neovascularization, cancer cell migration, adhesion, invasion and
metastasization. However, the clinical use of Δ(9)-THC and additional
cannabinoid agonists is often limited by their unwanted psychoactive side
effects, and for this reason interest in non-psychoactive cannabinoid compounds
with structural affinity for Δ(9)-THC, such as cannabidiol (CBD), has
substantially increased in recent years. The present review will focus on the
efficacy of CBD in the modulation of different steps of tumourigenesis in
several types of cancer and highlights the importance of exploring CBD/CBD
analogues as alternative therapeutic agents.
Cannabidiol inhibits angiogenesis by multiple mechanisms.
Solinas
M1, Massi
P, Cantelmo
AR, Cattaneo
MG, Cammarota
R, Bartolini
D, Cinquina
V, Valenti
M, Vicentini
LM, Noonan
DM, Albini
A, Parolaro
D
Several studies have demonstrated anti-proliferative and
pro-apoptotic actions of cannabinoids on various tumours, together with their
anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD)
effectively inhibits the growth of different types of tumours in vitro and in
vivo and down-regulates some pro-angiogenic signals produced by glioma cells.
As its anti-angiogenic properties have not been thoroughly investigated to
date, and given its very favourable pharmacological and toxicological profile,
here, we evaluated the ability of CBD to modulate tumour angiogenesis.
Firstly, we evaluated the effect of CBD on human umbilical
vein endothelial cell (HUVEC) proliferation and viability - through
[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS
analysis - and in vitro motility - both in a classical Boyden chamber test and
in a wound-healing assay. We next investigated CBD effects on different
angiogenesis-related proteins released by HUVECs, using an angiogenesis array
kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro
angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids
embedded into collagen gels, and further characterized its effects in vivo
using a Matrigel sponge model of angiogenesis in C57/BL6 mice.
CBD induced HUVEC cytostasis without inducing apoptosis,
inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in
vivo in Matrigel sponges. These effects were associated with the
down-modulation of several angiogenesis-related molecules.
This study reveals that CBD inhibits angiogenesis by
multiple mechanisms. Its dual effect on both tumour and endothelial cells
supports the hypothesis that CBD has potential as an effective agent in cancer
therapy.
Cannabidiol inhibits cancer cell invasion via
upregulation of tissue inhibitor of matrix metalloproteinases-1.
Although cannabinoids exhibit a broad variety of
anticarcinogenic effects, their potential use in cancer therapy is limited by
their psychoactive effects. Here we evaluated the impact of cannabidiol, a
plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using
Matrigel invasion assays we found a cannabidiol-driven impaired invasion of
human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was
reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient
receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol
appeared concomitantly with upregulation of tissue inhibitor of matrix
metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1
expression by siRNA led to a reversal of the cannabidiol-elicited decrease in
tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating
and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated
protein kinases were identified as upstream targets conferring TIMP-1 induction
and subsequent decreased invasiveness. Additionally, in vivo studies in
thymic-aplastic nude mice revealed a significant inhibition of A549 lung
metastasis in cannabidiol-treated animals as compared to vehicle-treated
controls. Altogether, these findings provide a novel mechanism underlying the
anti-invasive action of cannabidiol and imply its use as a therapeutic option
for the treatment of highly invasive cancers.
In vitro and in vivo efficacy of non-psychoactive
cannabidiol in neuroblastoma.
Fisher
T1, Golan
H2, Schiby
G3, PriChen
S4, Smoum
R5, Moshe
I1, Peshes-Yaloz
N6, Castiel
A6, Waldman
D2, Gallily
R7, Mechoulam
R5, Toren
A8.
Neuroblastoma (nbl) is one of the most common solid cancers
in children. Prognosis in advanced nbl is still poor despite aggressive
multimodality therapy. Furthermore, survivors experience severe long-term
multi-organ sequelae. Hence, the identification of new therapeutic strategies
is of utmost importance. Cannabinoids and their derivatives have been used for
years in folk medicine and later in the field of palliative care. Recently,
they were found to show pharmacologic activity in cancer, including cytostatic,
apoptotic, and antiangiogenic effects.
We investigated, in vitro and in vivo, the anti-nbl effect
of the most active compounds in Cannabis, Δ(9)-tetrahydrocannabinol (thc) and
cannabidiol (cbd). We set out to experimentally determine the effects of those
compounds on viability, invasiveness, cell cycle distribution, and programmed
cell death in human nbl SK-N-SH cells.
Both compounds have antitumourigenic activity in vitro and
impeded the growth of tumour xenografts in vivo. Of the two cannabinoids
tested, cbd was the more active. Treatment with cbd reduced the viability and
invasiveness of treated tumour cells in vitro and induced apoptosis (as
demonstrated by morphology changes, sub-G1 cell accumulation, and annexin V
assay). Moreover, cbd elicited an increase in activated caspase 3 in treated
cells and tumour xenografts.
Our results demonstrate the antitumourigenic action of cbd
on nbl cells. Because cbd is a nonpsychoactive cannabinoid that appears to be
devoid of side effects, our results support its exploitation as an effective
anticancer drug in the management of nbl.
The influence of biomechanical properties and
cannabinoids on tumor invasion.
Hohmann
T1, Grabiec
U1, Ghadban
C1, Feese
K1, Dehghani
F1.
Cannabinoids are known to have an anti-tumorous effect, but
the underlying mechanisms are only sparsely understood. Mechanical characteristics
of tumor cells represent a promising marker to distinguish between tumor cells
and the healthy tissue. We tested the hypothesis whether cannabinoids influence
the tumor cell specific mechanical and migratory properties and if these
factors are a prognostic marker for the invasiveness of tumor cells.
3 different glioblastoma cell lines were treated with
cannabinoids and changes of mechanical and migratory properties of single cells
were measured using atomic force microscopy and time lapse imaging. The
invasiveness of cell lines was determined using a co-culture model with
organotypic hippocampal slice cultures.
We found that cannabinoids are capable of influencing
migratory and mechanical properties in a cell line specific manner. A network
analysis revealed a correlation between a "generalized stiffness" and
the invasiveness for all tumor cell lines after 3 and 4 d of invasion
time: r3d = -0.88 [-0.52;-0.97]; r4d = -0.90
[-0.59;-0.98].
Here we could show that a "generalized stiffness"
is a profound marker for the invasiveness of a tumor cell population in our
model and thus might be of high clinical relevance for drug testing.
Additionally cannabinoids were shown to be of potential use for therapeutic
approaches of glioblastoma.
Antitumorigenic targets of cannabinoids - current status
and implications.
Molecular structures of the endocannabinoid system have
gained interest as potential pharmacotherapeutical targets for systemic cancer
treatment.
The present review covers the contribution of the
endocannabinoid system to cancer progression. Particular focus will be set on
the accumulating preclinical data concerning antimetastatic, anti-invasive and
anti-angiogenic mechanisms induced by cannabinoids.
The main goal of targeting endocannabinoid structures for
systemic anticancer treatment is the comparatively good safety profile of
cannabinoid compounds. In addition, antitumorigenic mechanisms of cannabinoids
are not restricted to a single molecular cascade but involve multiple effects
on various levels of cancer progression such as angiogenesis and metastasis.
Particularly the latter effect has gained interest for pharmacological
interventions. Thus, drugs aiming at the endocannabinoid system may represent
potential 'antimetastatics' for an upgrade of a future armamentarium against
cancer diseases.
Cannabinoids - a new weapon against cancer?
Pokrywka
M1, Góralska
J1, Solnica
B1.
Cannabis has been cultivated by man since Neolithic times.
It was used, among others for fiber and rope production, recreational purposes
and as an excellent therapeutic agent. The isolation and characterization of
the structure of one of the main active ingredients of cannabis - Δ9 -
tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors
CB1 and CB2, has been a milestone in the study of the possibilities of the uses
of Cannabis sativa and related products in modern medicine. Many scientific
studies indicate the potential use of cannabinoids in the fight against cancer.
Experiments carried out on cell lines in vitro and on animal models in vivo
have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and
their analogues can lead to inhibition of the growth of many tumor types,
exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively
influencing neo-angiogenesis and the ability of cells to metastasize. The main
molecular mechanism leading to inhibition of proliferation of cancer cells by
cannabinoids is apoptosis. Studies have shown, however, that the process of
apoptosis in cells, treated with recannabinoids, is a consequence of induction
of endoplasmic reticulum stress and autophagy. On the other hand, in the
cellular context and dosage dependence, cannabinoids may enhance the
proliferation of tumor cells by suppressing the immune system or by activating
mitogenic factors. Leading from this there is a an obvious need to further
explore cannabinoid associated molecular pathways making it possible to develop
safe therapeutic drug agents for patients in the future.
Cannabidiol, a novel inverse agonist for GPR12.
GPR12 is a constitutively active, Gs
protein-coupled receptor that currently has no confirmed endogenous ligands.
GPR12 may be involved in physiological processes such as maintenance of oocyte
meiotic arrest and brain development, as well as pathological conditions such
as metastatic cancer. In this study, the potential effects of various classes
of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data
demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid,
acted as an inverse agonist to inhibit cAMP accumulation stimulated by the
constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD.
The structure-activity relationship studies of CBD indicate that both the free
hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12.
Furthermore, studies using cholera toxin, which blocks Gs protein
and pertussis toxin, which blocks Gi protein, revealed that Gs,
but not Gi is involved in the inverse agonism of CBD on GPR12. CBD
is a promising novel therapeutic agent for cancer, and GPR12 has been shown to
alter viscoelasticity of metastatic cancer cells. Since we have demonstrated
that CBD is an inverse agonist for GPR12, this provides novel mechanism of
action for CBD, and an initial chemical scaffold upon which highly potent and
efficacious agents acting on GPR12 may be developed with the ultimate goal of
blocking cancer metastasis.
$8 for the book. Or FREE on Kindle Unlimited
BRAIN CANCER
A cannabis extract with THC and CBD improved survival of
patients with recurrent glioblastoma, a particularly aggressive brain tumour,
if given together with standard therapy. This is the result of a
placebo-controlled study with 21 patients, which was reported by the producer
of the cannabis extract Sativex, GW Pharmaceuticals from the UK. 12 patients
were randomized to receive Sativex together with temozolomide and 9 patients
received placebo together with temozolomide.
The study showed that 83% of patients with documented
recurrent glioblastoma treated with THC and CBD had survived the first year
compared with 53% of patients in the placebo group (p=0.042). Median survival
for the cannabis group was greater than 550 days compared with 369 days in the
placebo group. The press release says: “GW conducted substantial pre-clinical
oncologic research on several cannabinoids in various forms of cancer including
brain, lung, breast, pancreatic, melanoma, ovarian, gastric, renal, prostate
and bladder. These studies have resulted in approximately 15 publications and
show the multi-modal effects of cannabinoids on a number of the key pathways
associated with tumor growth and progression.”
Quantitative Analyses of Synergistic Responses between
Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of
Glioblastoma and Neural Progenitor Cells in Culture.
Evidence suggests that the nonpsychotropic cannabis-derived
compound, cannabidiol (CBD), has antineoplastic 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 antiproliferative 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 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. Cotreatment regimens combining CBD and
DNA-damaging agents produced synergistic antiproliferating 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.
Local delivery of cannabinoid-loaded microparticles
inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.
Hernán
Pérez de la Ossa D1, Lorente
M, Gil-Alegre
ME, Torres
S, García-Taboada
E, Aberturas
Mdel R, Molpeceres
J, Velasco
G, Torres-Suárez
AI.
Cannabinoids, the active components of marijuana and their
derivatives, are currently investigated due to their potential therapeutic
application for the management of many different diseases, including cancer.
Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two
major ingredients of marijuana - have been shown to inhibit tumor growth in a number
of animal models of cancer, including glioma. Although there are several
pharmaceutical preparations that permit the oral administration of THC or its
analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched
cannabis extract, the systemic administration of cannabinoids has several
limitations in part derived from the high lipophilicity exhibited by these
compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone
microparticles as an alternative delivery system for long-term cannabinoid
administration in a murine xenograft model of glioma. In vitro characterization
of THC- and CBD-loaded microparticles showed that this method of
microencapsulation facilitates a sustained release of the two cannabinoids for
several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC-
and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts
reduced tumour growth with the same efficacy than a daily local administration
of the equivalent amount of those cannabinoids in solution. Moreover, treatment
with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell
proliferation and angiogenesis in these tumours. Our findings support that THC-
and CBD-loaded microparticles could be used as an alternative method of
cannabinoid delivery in anticancer therapies.
Cannabidiol, a non-psychoactive cannabinoid compound,
inhibits proliferation and invasion in U87-MG and T98G glioma cells through a
multitarget effect.
Solinas
M1, Massi
P, Cinquina
V, Valenti
M, Bolognini
D, Gariboldi
M, Monti
E, Rubino
T, Parolaro
D.
In the present study, we found that CBD inhibited U87-MG and
T98G cell proliferation and invasiveness in vitro and caused a decrease in the
expression of a set of proteins specifically involved in growth, invasion and
angiogenesis. In addition, CBD treatment caused a dose-related down-regulation
of ERK and Akt prosurvival signaling pathways in U87-MG and T98G cells and
decreased hypoxia inducible factor HIF-1α expression in U87-MG cells. Taken
together, these results provide new insights into the antitumor action of CBD,
showing that this cannabinoid affects multiple tumoral features and molecular
pathways. As CBD is a non-psychoactive phytocannabinoid that appears to be devoid
of side effects, our results support its exploitation as an effective
anti-cancer drug in the management of gliomas.
Triggering of the TRPV2 channel by cannabidiol sensitizes
glioblastoma cells to cytotoxic chemotherapeutic agents.
The aggressive behavior of Glioblastoma multiforme (GBM) is
mainly due to high invasiveness and proliferation rate as well as to high
resistance to standard chemotherapy. Several chemotherapeutic agents like
temozolomide (TMZ), carmustine (BCNU) or doxorubicin (DOXO) have been employed
for treatment of GBM, but they display limited efficacy. Therefore, it is
important to identify new treatment modalities to improve therapeutic effects
and enhance GBM chemosensitivity. Recently, activation of the transient receptor
potential vanilloid type 2 (TRPV2) has been found to inhibit human GBM cell
proliferation and overcome BCNU resistance of GBM cells. Herein, we evaluated
the involvement of cannabidiol (CBD)-induced TRPV2 activation, in the
modulation of glioma cell chemosensitivity to TMZ, BCNU and DOXO. We found that
CBD increases TRPV2 expression and activity. CBD by triggering TRPV2-dependent
Ca(2+) influx increases drug uptake and synergizes with cytotoxic agents to
induce apoptosis of glioma cells, whereas no effects were observed in normal
human astrocytes. Moreover, as the pore region of transient receptor potential
(TRP) channels is critical for ion channel permeation, we demonstrated that
deletion of TRPV2 poredomain inhibits CBD-induced Ca(2+) influx, drug uptake
and cytotoxic effects. Overall, we demonstrated that co-administration of
cytotoxic agents together with the TRPV2 agonist CBD increases drug uptake and
parallelly potentiates cytotoxic activity in human glioma cells.
Id-1 is a key transcriptional regulator of glioblastoma
aggressiveness and a novel therapeutic target.
Soroceanu
L1, Murase
R, Limbad
C, Singer
E, Allison
J, Adrados
I, Kawamura
R, Pakdel
A, Fukuyo
Y, Nguyen
D, Khan
S, Arauz
R, Yount
GL, Moore
DH, Desprez
PY, McAllister
SD.
Glioblastoma is the most common form of primary adult brain
tumors. A majority of glioblastomas grow invasively into distant brain tissue,
leading to tumor recurrence, which is ultimately incurable. It is, therefore,
essential to discover master regulators that control glioblastoma invasiveness
and target them therapeutically. We show here that the transcriptional
regulator Id-1 plays a critical role in modulating the invasiveness of
glioblastoma cell lines and primary glioblastoma cells. Id-1 expression levels
positively correlate with glioma cell invasiveness in culture and with
histopathologic grades in patient biopsies. Id-1 knockdown dramatically reduces
glioblastoma cell invasion that is accompanied by profound morphologic changes
and robust reduction in expression levels of "mesenchymal" markers,
as well as inhibition of self-renewal potential and downregulation of glioma
stem cell markers. Importantly, genetic knockdown of Id-1 leads to a
significant increase in survival in an orthotopic model of human glioblastoma.
Furthermore, we show that a nontoxic compound, cannabidiol, significantly
downregulates Id-1 gene expression and associated glioma cell invasiveness and
self-renewal. In addition, cannabidiol significantly inhibits the invasion of
glioblastoma cells through an organotypic brain slice and glioma progression in
vivo. Our results suggest that Id-1 regulates multiple tumor-promoting pathways
in glioblastoma and that drugs targeting Id-1 represent a novel and promising
strategy for improving the therapy and outcome of patients with glioblastoma.
Cannabidiol inhibits human glioma cell migration through
a cannabinoid receptor-independent mechanism.
We evaluated the ability of cannabidiol (CBD) to impair the
migration of tumor cells stimulated by conditioned medium. CBD caused
concentration-dependent inhibition of the migration of U87 glioma cells,
quantified in a Boyden chamber. Since these cells express both cannabinoid CB1
and CB2 receptors in the membrane, we also evaluated their engagement in the
antimigratory effect of CBD. The inhibition of cell was not antagonized either
by the selective cannabinoid receptor antagonists SR141716 (CB1) and SR144528
(CB2) or by pretreatment with pertussis toxin, indicating no involvement of
classical cannabinoid receptors and/or receptors coupled to Gi/o proteins.
These results reinforce the evidence of antitumoral properties of CBD,
demonstrating its ability to limit tumor invasion, although the mechanism of
its pharmacological effects remains to be clarified.
Systematic review of the literature on clinical and
experimental trials on the antitumor effects of cannabinoids in gliomas.
To evaluate, through a systematic review of the literature,
the antitumoral effects of cannabinoids on gliomas. Research included the
following electronic databases: PUBMED, EMBASE, LILACS and The Cochrane
Collaboration Controlled Trials Register. All published studies involving the
antitumoral effects (cellular and molecular mechanisms) of cannabinoids were
considered for this review. The bibliography search strategy included all
publications of each of these databases until December 31, 2012. From 2,260
initially identified articles, 35 fulfilled the inclusion criteria for this
review. All the studies included in this systematic review were experimental
(in vivo and/or in vitro), except for one pilot clinical trial phase I/II
involving humans. In all experimental studies included, cannabinoids exerted
antitumoral activity in vitro and/or antitumoral evidence in vivo in several
models of tumor cells and tumors. The antitumor activity included:
antiproliferative effects (cell cycle arrest), decreased viability and cell
death by toxicity, apoptosis, necrosis, autophagy, as well as antiangiogenic
and antimigratory effects. Antitumoral evidence included: reduction in tumor
size, antiangiogenic, and antimetastatic effects. Additionally, most of the
studies described that the canabinnoids exercised selective antitumoral action
in several distinct tumor models. Thereby, normal cells used as controls were
not affected. The safety factor in the cannabinoids' administration has also
been demonstrated in vivo. The various cannabinoids tested in multiple tumor
models showed antitumoral effects both in vitro and in vivo. These findings
indicate that cannabinoids are promising compounds for the treatment of
gliomas.
Antitumor effects of cannabidiol, a nonpsychoactive
cannabinoid, on human glioma cell lines.
Recently, cannabinoids (CBs) have been shown to possess
antitumor properties. Because the psychoactivity of cannabinoid compounds
limits their medicinal usage, we undertook the present study to evaluate the in
vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive
cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of
CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism
[3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and
viability in glioma cells, in a concentration-dependent manner that was already
evident 24 h after CBD exposure, with an apparent IC(50) of 25 microM. The
antiproliferative effect of CBD was partially prevented by the CB2 receptor
antagonist
N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide
(SR144528; SR2) and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor
antagonist
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide
hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the
inhibitors of ceramide generation, or pertussis toxin did not counteract CBD
effects. We also show, for the first time, that the antiproliferative effect of
CBD was correlated to induction of apoptosis, as determined by cytofluorimetric
analysis and single-strand DNA staining, which was not reverted by cannabinoid
antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5
mg/mouse, significantly inhibited the growth of subcutaneously implanted U87
human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce
a significant antitumor activity both in vitro and in vivo, thus suggesting a
possible application of CBD as an antineoplastic agent.
Cannabidiol enhances the inhibitory effects of
delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and
survival.
Marcu
JP1, Christian
RT, Lau
D, Zielinski
AJ, Horowitz
MP, Lee
J, Pakdel
A, Allison
J, Limbad
C, Moore
DH, Yount
GL, Desprez
PY, McAllister
SD.
The cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor
agonist Delta(9)-tetrahydrocannabinol (THC) has been shown to be a broad-range
inhibitor of cancer in culture and in vivo, and is currently being used in a
clinical trial for the treatment of glioblastoma. It has been suggested that
other plant-derived cannabinoids, which do not interact efficiently with CB(1)
and CB(2) receptors, can modulate the actions of Delta(9)-THC. There are
conflicting reports, however, as to what extent other cannabinoids can modulate
Delta(9)-THC activity, and most importantly, it is not clear whether other
cannabinoid compounds can either potentiate or inhibit the actions of
Delta(9)-THC. We therefore tested cannabidiol, the second most abundant
plant-derived cannabinoid, in combination with Delta(9)-THC. In the U251 and
SF126 glioblastoma cell lines, Delta(9)-THC and cannabidiol acted
synergistically to inhibit cell proliferation. The treatment of glioblastoma
cells with both compounds led to significant modulations of the cell cycle and
induction of reactive oxygen species and apoptosis as well as specific
modulations of extracellular signal-regulated kinase and caspase activities.
These specific changes were not observed with either compound individually,
indicating that the signal transduction pathways affected by the combination
treatment were unique. Our results suggest that the addition of cannabidiol to Delta(9)-THC
may improve the overall effectiveness of Delta(9)-THC in the treatment of
glioblastoma in cancer patients.
BREAST CANCER
Cannabidiolic acid-mediated selective down-regulation of
c-fos in highly aggressive breast cancer MDA-MB-231 cells: possible involvement
of its down-regulation in the abrogation of aggressiveness.
The physiological activities of cannabidiolic acid (CBDA), a
component of fiber-type cannabis plants, have been demonstrated and include its
function as a protector against external invasion by inducing
cannabinoid-mediated necrosis (Shoyama et al., Plant Signal Behav 3:1111-1112,
2008). The biological activities of CBDA have been attracting increasing
attention. We previously identified CBDA as an inhibitor of the migration of
MDA-MB-231 cells, a widely used human breast cancer cell line in cancer biology,
due to its highly aggressive nature. The chemical inhibition and
down-regulation of cyclooxygenase-2 (COX-2), the expression of which has been
detected in ~40 % of human invasive breast cancers, are suggested to be
involved in the CBDA-mediated abrogation of cell migration. However, the
molecular mechanism(s) responsible for the CBDA-induced down-regulation of
COX-2 in MDA-MB-231 cells have not yet been elucidated. In the present study,
we describe a possible mechanism by which CBDA abrogates the expression of
COX-2 via the selective down-regulation of c-fos, one component of the
activator protein-1 (AP-1) dimer complex, a transcription factor for the
positive regulation of the COX-2 gene.
Cannabidiolic acid, a major cannabinoid in fiber-type
cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration.
Takeda
S1, Okajima
S, Miyoshi
H, Yoshida
K, Okamoto
Y, Okada
T, Amamoto
T, Watanabe
K, Omiecinski
CJ, Aramaki
H.
Cannabidiol (CBD), a major non-psychotropic constituent of
fiber-type cannabis plant, has been reported to possess diverse biological
activities, including anti-proliferative effect on cancer cells. Although CBD
is obtained from non-enzymatic decarboxylation of its parent molecule,
cannabidiolic acid (CBDA), few studies have investigated whether CBDA itself is
biologically active. Results of the current investigation revealed that CBDA
inhibits migration of the highly invasive MDA-MB-231 human breast cancer cells,
apparently through a mechanism involving inhibition of cAMP-dependent protein
kinase A, coupled with an activation of the small GTPase, RhoA. It is
established that activation of the RhoA signaling pathway leads to inhibition
of the mobility of various cancer cells, including MDA-MB-231 cells. The data
presented in this report suggest for the first time that as an active component
in the cannabis plant, CBDA offers potential therapeutic modality in the
abrogation of cancer cell migration, including aggressive breast cancers.
Cannabidiol as a novel inhibitor of Id-1 gene expression
in aggressive breast cancer cells.
Invasion and metastasis of aggressive breast cancer cells is
the final and fatal step during cancer progression, and is the least understood
genetically. Clinically, there are still limited therapeutic interventions for
aggressive and metastatic breast cancers available. Clearly, effective and
nontoxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix
transcription factors, has recently been shown to be a key regulator of the
metastatic potential of breast and additional cancers. Using a mouse model, we
previously determined that metastatic breast cancer cells became significantly
less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated
by stable transduction with antisense Id-1. It is not possible at this point,
however, to use antisense technology to reduce Id-1 expression in patients with
metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid
with a low-toxicity profile, could down-regulate Id-1 expression in aggressive
human breast cancer cells. The CBD concentrations effective at inhibiting Id-1
expression correlated with those used to inhibit the proliferative and invasive
phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at
the mRNA and protein level in a concentration-dependent fashion. These effects
seemed to occur as the result of an inhibition of the Id-1 gene at the promoter
level. Importantly, CBD did not inhibit invasiveness in cells that ectopically
expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous
agent that can significantly decrease Id-1 expression in metastatic breast
cancer cells leading to the down-regulation of tumor aggressiveness.
Pathways mediating the effects of cannabidiol on the
reduction of breast cancer cell proliferation, invasion, and metastasis.
McAllister
SD1, Murase
R, Christian
RT, Lau
D, Zielinski
AJ, Allison
J, Almanza
C, Pakdel
A, Lee
J, Limbad
C, Liu
Y, Debs
RJ, Moore
DH, Desprez
PY.
Invasion and metastasis of aggressive breast cancer cells
are the final and fatal steps during cancer progression. Clinically, there are
still limited therapeutic interventions for aggressive and metastatic breast
cancers available. Therefore, effective, targeted, and non-toxic therapies are
urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription
factors, has recently been shown to be a key regulator of the metastatic
potential of breast and additional cancers. We previously reported that
cannabidiol (CBD), a cannabinoid with a low toxicity profile, down-regulated
Id-1 gene expression in aggressive human breast cancer cells in culture. Using
cell proliferation and invasion assays, cell flow cytometry to examine cell
cycle and the formation of reactive oxygen species, and Western analysis, we
determined pathways leading to the down-regulation of Id-1 expression by CBD
and consequently to the inhibition of the proliferative and invasive phenotype
of human breast cancer cells. Then, using the mouse 4T1 mammary tumor cell line
and the ranksum test, two different syngeneic models of tumor metastasis to the
lungs were chosen to determine whether treatment with CBD would reduce
metastasis in vivo. We show that CBD inhibits human breast cancer cell
proliferation and invasion through differential modulation of the extracellular
signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and
that both pathways lead to down-regulation of Id-1 expression. Moreover, we
demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using
immune competent mice, we then show that treatment with CBD significantly
reduces primary tumor mass as well as the size and number of lung metastatic
foci in two models of metastasis. Our data demonstrate the efficacy of CBD in
pre-clinical models of breast cancer. The results have the potential to lead to
the development of novel non-toxic compounds for the treatment of breast cancer
metastasis, and the information gained from these experiments broaden our
knowledge of both Id-1 and cannabinoid biology as it pertains to cancer
progression
Cannabidiol induces programmed cell death in breast
cancer cells by coordinating the cross-talk between apoptosis and autophagy.
Cannabidiol (CBD), a major nonpsychoactive constituent of
cannabis, is considered an antineoplastic agent on the basis of its in vitro
and in vivo activity against tumor cells. However, the exact molecular
mechanism through which CBD mediates this activity is yet to be elucidated.
Here, we have shown CBD-induced cell death of breast cancer cells, independent
of cannabinoid and vallinoid receptor activation. Electron microscopy revealed
morphologies consistent with the coexistence of autophagy and apoptosis.
Western blot analysis confirmed these findings. We showed that CBD induces
endoplasmic reticulum stress and, subsequently, inhibits AKT and mTOR signaling
as shown by decreased levels of phosphorylated mTOR and 4EBP1, and cyclin D1.
Analyzing further the cross-talk between the autophagic and apoptotic signaling
pathways, we found that beclin1 plays a central role in the induction of
CBD-mediated apoptosis in MDA-MB-231 breast cancer cells. Although CBD enhances
the interaction between beclin1 and Vps34, it inhibits the association between
beclin1 and Bcl-2. In addition, we showed that CBD reduces mitochondrial
membrane potential, triggers the translocation of BID to the mitochondria, the
release of cytochrome c to the cytosol, and, ultimately, the activation of the
intrinsic apoptotic pathway in breast cancer cells. CBD increased the
generation of reactive oxygen species (ROS), and ROS inhibition blocked the
induction of apoptosis and autophagy. Our study revealed an intricate interplay
between apoptosis and autophagy in CBD-treated breast cancer cells and
highlighted the value of continued investigation into the potential use of CBD
as an antineoplastic agent
Antitumor activity of plant cannabinoids with emphasis on
the effect of cannabidiol on human breast carcinoma.
Ligresti
A1, Moriello
AS, Starowicz
K, Matias
I, Pisanti
S, De
Petrocellis L, Laezza
C, Portella
G, Bifulco
M, Di
Marzo V.
Delta(9)-Tetrahydrocannabinol (THC) exhibits antitumor
effects on various cancer cell types, but its use in chemotherapy is limited by
its psychotropic activity. We investigated the antitumor activities of other
plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene,
cannabidiol acid and THC acid, and assessed whether there is any advantage in
using Cannabis extracts (enriched in either cannabidiol or THC) over pure
cannabinoids. Results obtained in a panel of tumor cell lines clearly indicate
that, of the five natural compounds tested, cannabidiol is the most potent
inhibitor of cancer cell growth (IC(50) between 6.0 and 10.6 microM), with
significantly lower potency in noncancer cells. The cannabidiol-rich extract
was equipotent to cannabidiol, whereas cannabigerol and cannabichromene
followed in the rank of potency. Both cannabidiol and the cannabidiol-rich
extract inhibited the growth of xenograft tumors obtained by s.c. injection
into athymic mice of human MDA-MB-231 breast carcinoma or rat
v-K-ras-transformed thyroid epithelial cells and reduced lung metastases
deriving from intrapaw injection of MDA-MB-231 cells. Judging from several
experiments on its possible cellular and molecular mechanisms of action, we
propose that cannabidiol lacks a unique mode of action in the cell lines
investigated. At least for MDA-MB-231 cells, however, our experiments indicate
that cannabidiol effect is due to its capability of inducing apoptosis via:
direct or indirect activation of cannabinoid CB(2) and vanilloid transient
receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid
receptor-independent elevation of intracellular Ca(2+) and reactive oxygen
species. Our data support the further testing of cannabidiol and cannabidiol-rich
extracts for the potential treatment of cancer.
COLON CANCER
Chemopreventive effect of the non-psychotropic
phytocannabinoid cannabidiol on experimental colon cancer.
Colon cancer affects millions of individuals in Western
countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis
sativa, exerts pharmacological actions (antioxidant and intestinal
antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic
degradation) potentially beneficial for colon carcinogenesis. Thus, we
investigated its possible chemopreventive effect in the model of colon cancer
induced by azoxymethane (AOM) in mice. AOM treatment was associated with
aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation,
up-regulation of phospho-Akt, iNOS and COX-2 and down-regulation of caspase-3.
Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced
phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines,
cannabidiol protected DNA from oxidative damage, increased endocannabinoid
levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists
sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect
in vivo and reduces cell proliferation through multiple mechanisms.
Induction of apoptosis by cannabinoids in prostate and
colon cancer cells is phosphatase dependent.
We hypothesized that the anticancer activity of cannabinoids
was linked to induction of phosphatases.
The effects of cannabidiol (CBD) and the synthetic
cannabinoid WIN-55,212 (WIN) on LNCaP (prostate) and SW480 (colon) cancer cell
proliferation were determined by cell counting; apoptosis was determined by
cleavage of poly(ADP)ribose polymerase (PARP) and caspase-3 (Western blots);
and phosphatase mRNAs were determined by real-time PCR. The role of phosphatases
and cannabinoid receptors in mediating CBD- and WIN-induced apoptosis was
determined by inhibition and receptor knockdown.
CBD and WIN inhibited LNCaP and SW480 cell growth and
induced mRNA expression of several phosphatases, and the phosphatase inhibitor
sodium orthovanadate significantly inhibited cannabinoid-induced PARP cleavage
in both cell lines, whereas only CBD-induced apoptosis was CB1 and CB2
receptor-dependent.
Cannabinoid receptor agonists induce phosphatases and
phosphatase-dependent apoptosis in cancer cell lines; however, the role of the
CB receptor in mediating this response is ligand-dependent.
ENDOCRINE CANCER
Endocannabinoids in endocrine and related tumours.
The 'endocannabinoid system', comprising the cannabinoid CB1
and CB2 receptors, their endogenous ligands, endocannabinoids and the enzymes
that regulate their biosynthesis and degradation, has drawn a great deal of
scientist attention during the last two decades. The endocannabinoid system is
involved in a broad range of functions and in a growing number of
physiopathological conditions. Indeed, recent evidence indicates that
endocannabinoids influence the intracellular events controlling the
proliferation of numerous types of endocrine and related cancer cells, thereby
leading to both in vitro and in vivo antitumour effects. In particular, they
are able to inhibit cell growth, invasion and metastasis of thyroid, breast and
prostate tumours. The chief events of endocannabinoids in cancer cell
proliferation are reported highlighting the correspondent signalling involved
in tumour processes: regulation of adenylyl cyclase, cyclic AMP-protein
kinase-A pathway and MEK-extracellular signal-regulated kinase signalling
cascade.
A comparative study on cannabidiol-induced apoptosis in
murine thymocytes and EL-4 thymoma cells.
It has been shown that leukemia and glioma cells are
sensitive to cannabidiol (CBD)-induced apoptosis, whereas primary monocytes and
glia cells are relatively insensitive. In the current study, the cellular
events and sensitivity to CBD-induced apoptosis between murine thymocytes and
EL-4 thymoma cells were compared. Cannabidiol markedly induced apoptosis in a
time- and concentration-related manner in both cells. The efficacy of CBD to induce
apoptosis was comparable between the 2 types of T cells, whereas CBD induced
apoptosis in thymocytes with a slightly greater potency than in EL4 cells.
Time-course analyses revealed CBD-mediated apoptosis occurred earlier in EL-4
cells than that in thymocytes. An increased level of cellular reactive oxygen
species (ROS) was detected in both cells with the peak response at 2 h post CBD
treatment. Concordantly, CBD triggered a gradual diminishment in the cellular
thiols. The presence of N-acetyl-L-cysteine (NAC), a precursor of glutathione,
markedly attenuated the induction of apoptosis, and restored the diminished
levels of cellular thiols. The results demonstrated that both thymocytes and
EL-4 thymoma cells were susceptible to CBD-induced apoptosis and that ROS
played a critical role in the apoptosis induction.
KAPOSI SARCOMA
Cannabidiol inhibits growth and induces programmed cell
death in kaposi sarcoma-associated herpesvirus-infected endothelium.
Kaposi sarcoma is the most common neoplasm caused by Kaposi
sarcoma-associated herpesvirus (KSHV). It is prevalent among the elderly in the
Mediterranean, inhabitants of sub-Saharan Africa, and immunocompromised
individuals such as organ transplant recipients and AIDS patients. Current
treatments for Kaposi sarcoma can inhibit tumor growth but are not able to
eliminate KSHV from the host. When the host's immune system weakens, KSHV
begins to replicate again, and active tumor growth ensues. New therapeutic
approaches are needed. Cannabidiol (CBD), a plant-derived cannabinoid, exhibits
promising antitumor effects without inducing psychoactive side effects. CBD is
emerging as a novel therapeutic for various disorders, including cancer. In
this study, we investigated the effects of CBD both on the infection of
endothelial cells (ECs) by KSHV and on the growth and apoptosis of
KSHV-infected ECs, an in vitro model for the transformation of normal
endothelium to Kaposi sarcoma. While CBD did not affect the efficiency with
which KSHV infected ECs, it reduced proliferation and induced apoptosis in
those infected by the virus. CBD inhibited the expression of KSHV viral G
protein-coupled receptor (vGPCR), its agonist, the chemokine growth-regulated
protein α (GRO-α), vascular endothelial growth factor receptor 3 (VEGFR-3), and
the VEGFR-3 ligand, vascular endothelial growth factor C (VEGF-C). This
suggests a potential mechanism by which CBD exerts its effects on KSHV-infected
endothelium and supports the further examination of CBD as a novel targeted
agent for the treatment of Kaposi sarcoma.
LEUKEMIA
Cannabidiol-induced apoptosis in human leukemia cells: A
novel role of cannabidiol in the regulation of p22phox and Nox4 expression.
In the current study, we examined the effects of the
nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in
leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid
receptor 2 (CB2)-mediated reduction in cell viability and induction in
apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in
tumor burden and an increase in apoptotic tumors in vivo. From a mechanistic
standpoint, cannabidiol exposure resulted in activation of caspase-8, caspase-9,
and caspase-3, cleavage of poly(ADP-ribose) polymerase, and a decrease in
full-length Bid, suggesting possible cross-talk between the intrinsic and
extrinsic apoptotic pathways. The role of the mitochondria was further
suggested as exposure to cannabidiol led to loss of mitochondrial membrane
potential and release of cytochrome c. It is noteworthy that cannabidiol
exposure led to an increase in reactive oxygen species (ROS) production as well
as an increase in the expression of the NAD(P)H oxidases Nox4 and p22(phox).
Furthermore, cannabidiol-induced apoptosis and reactive oxygen species (ROS)
levels could be blocked by treatment with the ROS scavengers or the NAD(P)H
oxidase inhibitors. Finally, cannabidiol exposure led to a decrease in the
levels of p-p38 mitogen-activated protein kinase, which could be blocked by
treatment with a CB2-selective antagonist or ROS scavenger. Together, the
results from this study reveal that cannabidiol, acting through CB2 and
regulation of Nox4 and p22(phox) expression, may be a novel and highly
selective treatment for leukemia.
Cannabidiol-induced apoptosis in human leukemia cells: A
novel role of cannabidiol in the regulation of p22phox and Nox4 expression.
In the current study, we examined the effects of the
nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in
leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid
receptor 2 (CB2)-mediated reduction in cell viability and induction in
apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in
tumor burden and an increase in apoptotic tumors in vivo. From a mechanistic
standpoint, cannabidiol exposure resulted in activation of caspase-8,
caspase-9, and caspase-3, cleavage of poly(ADP-ribose) polymerase, and a
decrease in full-length Bid, suggesting possible cross-talk between the
intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was
further suggested as exposure to cannabidiol led to loss of mitochondrial
membrane potential and release of cytochrome c. It is noteworthy that
cannabidiol exposure led to an increase in reactive oxygen species (ROS)
production as well as an increase in the expression of the NAD(P)H oxidases
Nox4 and p22(phox). Furthermore, cannabidiol-induced apoptosis and reactive
oxygen species (ROS) levels could be blocked by treatment with the ROS
scavengers or the NAD(P)H oxidase inhibitors. Finally, cannabidiol exposure led
to a decrease in the levels of p-p38 mitogen-activated protein kinase, which
could be blocked by treatment with a CB2-selective antagonist or ROS scavenger.
Together, the results from this study reveal that cannabidiol, acting through
CB2 and regulation of Nox4 and p22(phox) expression, may be a novel and highly
selective treatment for leukemia.
Cannabidiol Reduces Leukemic Cell Size - But Is It
Important?
The anti-cancer effect of the plant-derived cannabinoid,
cannabidiol, has been widely demonstrated both in vivo and in vitro.
However, this body of preclinical work has not been translated into clinical
use. Key issues around this failure can be related to narrow dose effects, the
cell model used and incomplete efficacy. A model of acute lymphoblastic
disease, the Jurkat T cell line, has been used extensively to study the
cannabinoid system in the immune system and cannabinoid-induced apoptosis.
Using these cells, this study sought to investigate the outcome of those
remaining viable cells post-treatment with cannabidiol, both in terms of cell
size and tracking any subsequent recovery. The phosphorylation status of the
mammalian Target of Rapamycin (mTOR) signaling pathway and the downstream
target ribosomal protein S6, were measured. The ability of cannabidiol to exert
its effect on cell viability was also evaluated in physiological oxygen
conditions. Cannabidiol reduced cell viability incompletely, and slowed the
cell cycle with fewer cells in the G2/M phase of the cell cycle. Cannabidiol
reduced phosphorylation of mTOR, PKB and S6 pathways related to survival and
cell size. The remaining population of viable cells that were cultured in
nutrient rich conditions post-treatment were able to proliferate, but did not
recover to control cell numbers. However, the proportion of viable cells that
were gated as small, increased in response to cannabidiol and normally sized
cells decreased. This proportion of small cells persisted in the recovery
period and did not return to basal levels. Finally, cells grown in 12% oxygen
(physiological normoxia) were more resistant to cannabidiol. In conclusion,
these results indicate that cannabidiol causes a reduction in cell size, which
persists post-treatment. However, resistance to cannabidiol under physiological
normoxia for these cells would imply that cannabidiol may not be useful in the
clinic as an anti-leukemic agent.
LUNG CANCER
Cannabidiol inhibits lung cancer cell invasion and
metastasis via intercellular adhesion molecule-1.
Ramer
R1, Bublitz
K, Freimuth
N, Merkord
J, Rohde
H, Haustein
M, Borchert
P, Schmuhl
E, Linnebacher
M, Hinz
B.
Cannabinoids inhibit cancer cell invasion via increasing
tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates
the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In
the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM)
elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via
cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44
mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549
was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1
induction became significant after 2 h, whereas significant TIMP-1 mRNA
increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or
siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of
CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and
R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls.
ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary
tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a
2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as
compared to vehicle-treated animals, and an antimetastatic effect that was
fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung
nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6%
for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce
ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer
cell invasiveness.
COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of
human lung cancer cells.
The antitumorigenic mechanism of cannabidiol is still
controversial. This study investigates the role of COX-2 and PPAR-γ in
cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell
lines (A549, H460) and primary cells from a patient with lung cancer,
cannabidiol elicited decreased viability associated with apoptosis. Apoptotic
cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662
(PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced
apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein
expression with a maximum induction of COX-2 mRNA after 8 hours and continuous
increases of PPAR-γ mRNA when compared with vehicle. In response to
cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent
prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2)
(15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a
PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice,
cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor
regression that was reversible by GW9662. Together, our data show a novel
proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2
and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent
PGs.
Decrease of plasminogen activator inhibitor-1 may
contribute to the anti-invasive action of cannabidiol on human lung cancer
cells.
Using human lung cancer cells, we evaluated the involvement
of plasminogen activator inhibitor-1 (PAI-1) in the anti-invasive action of
cannabidiol, a non-psychoactive cannabinoid.
Invasion was quantified by a modified Boyden chamber assay.
PAI-1 protein in cell culture media and PAI-1 mRNA were determined by
immunoblotting and RT-PCR, respectively.
Cannabidiol caused a profound inhibition of A549 cell
invasion, accompanied by a decreased expression and secretion of PAI-1.
Cannabidiol's effects on PAI-1 secretion and invasion were suppressed by
antagonists to CB(1) and CB(2) receptors as well as to transient receptor
potential vanilloid 1. Recombinant human PAI-1 and PAI-1 siRNA led to a
concentration-dependent up- and down-regulation of invasiveness, respectively,
suggesting a crucial role of PAI-1 in A549 invasiveness. Evidence for a causal
link between cannabidiol's effects on PAI-1 and invasion was provided by
experiments showing a reversal of its anti-invasive action by addition of
recombinant PAI-1 at non-proinvasive concentrations. Key data were confirmed in
two other human lung cancer cell lines (H460, H358). In vivo, a significant
downregulation of PAI-1 protein by cannabidiol was demonstrated in A549
xenografts.
Our data provide evidence for a hitherto unknown mechanism
underlying the anti-invasive action of cannabidiol on human lung cancer cells.
Media Ignored Expert's Shocking Findings That Marijuana
Helps Prevent Lung Cancer: Now It's Med-School Material
UCLA professor Donald Tashkin will share his research
discoveries
“Much of Tashkin's talk at Asilomar was devoted to chronic
obstructive pulmonary disease, another condition prevalent among tobacco
smokers. Chronic bronchitis and emphysema are two forms of COPD, which is the
fourth leading cause of death in the United States. Air pollution and tobacco
smoke are known culprits. Inhaled pathogens cause an inflammatory response,
resulting in diminished lung function. COPD patients have increasing difficulty
clearing the airways as they get older.
Tashkin and colleagues at UCLA conducted a major study in
which they measured lung function of various cohorts over eight years and found
that tobacco-only smokers had an accelerated rate of decline, but marijuana
smokers -- even if they smoked tobacco as well -- experienced the same rate of
decline as non-smokers. "The more tobacco smoked, the greater the rate of
decline," said Tashkin. "In contrast, no matter how much marijuana
was smoked, the rate of decline was similar to normal." Tashkin concluded
that his and other studies "do not support the concept that regular
smoking of marijuana leads to COPD."”
CANCER RELATED PAIN
Multicenter, double-blind, randomized,
placebo-controlled, parallel-group study of the efficacy, safety, and
tolerability of THC:CBD extract and THC extract in patients with intractable
cancer-related pain.
This study compared the efficacy of a tetrahydrocannabinol:cannabidiol
(THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and
a THC extract, with placebo, in relieving pain in patients with advanced
cancer. In total, 177 patients with cancer pain, who experienced inadequate
analgesia despite chronic opioid dosing, entered a two-week, multicenter,
double-blind, randomized, placebo-controlled, parallel-group trial. Patients
were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo
(n = 59). The primary analysis of change from baseline in mean pain Numerical
Rating Scale (NRS) score was statistically significantly in favor of THC:CBD
compared with placebo (improvement of -1.37 vs. -0.69), whereas the THC group
showed a nonsignificant change (-1.01 vs. -0.69). Twice as many patients taking
THC:CBD showed a reduction of more than 30% from baseline pain NRS score when
compared with placebo (23 [43%] vs. 12 [21%]). The associated odds ratio was
statistically significant, whereas the number of THC group responders was
similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical
significance. There was no change from baseline in median dose of opioid
background medication or mean number of doses of breakthrough medication across
treatment groups. No significant group differences were found in the NRS sleep
quality or nausea scores or the pain control assessment. However, the results
from the European Organisation for Research and Treatment of Cancer Quality of
Life Cancer Questionnaire showed a worsening in nausea and vomiting with
THC:CBD compared with placebo (P = 0.02), whereas THC had no difference (P =
1.0). Most drug-related adverse events were mild/moderate in severity. This
study shows that THC:CBD extract is efficacious for relief of pain in patients
with advanced cancer pain not fully relieved by strong opioids.
Nabiximols for opioid-treated cancer patients with
poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose
trial.
Portenoy
RK1, Ganae-Motan
ED, Allende
S, Yanagihara
R, Shaiova
L, Weinstein
S, McQuade
R, Wright
S, Fallon
MT.
Patients with advanced cancer who have pain that responds
poorly to opioid therapy pose a clinical challenge. Nabiximols (Nabiximols is
the U.S. Adopted Name [USAN] for Sativex [GW Pharma Ltd, Wiltshire, U.K.],
which does not yet have an INN), a novel cannabinoid formulation, is undergoing
investigation as add-on therapy for this population. In a randomized, double-blind,
placebo-controlled, graded-dose study, patients with advanced cancer and
opioid-refractory pain received placebo or nabiximols at a low dose (1-4
sprays/day), medium dose (6-10 sprays/day), or high dose (11-16 sprays/day).
Average pain, worst pain and sleep disruption were measured daily during 5
weeks of treatment; other questionnaires measured quality of life and mood. A
total of 360 patients were randomized; 263 completed. There were no baseline
differences across groups. The 30% responder rate primary analysis was not
significant for nabiximols versus placebo (overall P = .59). A secondary
continuous responder analysis of average daily pain from baseline to end of
study demonstrated that the proportion of patients reporting analgesia was
greater for nabiximols than placebo overall (P = .035), and specifically in the
low-dose (P = .008) and medium-dose (P = .039) groups. In the low-dose group,
results were similar for mean average pain (P = .006), mean worst pain (P =
.011), and mean sleep disruption (P = .003). Other questionnaires showed no
significant group differences. Adverse events were dose-related and only the
high-dose group compared unfavorably with placebo. This study supports the
efficacy and safety of nabiximols at the 2 lower-dose levels and provides
important dose information for future trials.
Nabiximols, a novel cannabinoid formulation, may be a useful
add-on analgesic for patients with opioid-refractory cancer pain. A randomized,
double-blind, placebo-controlled, graded-dose study demonstrated efficacy and
safety at low and medium doses.
PROSTATE CANCER
Towards the use of non-psychoactive cannabinoids for
prostate cancer.
Pacher
P1.
The palliative effects of Cannabis sativa (marijuana), and
its putative main active ingredient, Δ(9) -tetrahydrocannabinol (THC), which
include appetite stimulation, attenuation of nausea and emesis associated with
chemo- or radiotherapy, pain relief, mood elevation, and relief from insomnia
in cancer patients, are well-known. Because of the adverse psychoactive effects
of THC, numerous recent preclinical studies have been focused on investigating
other non-psychoactive constituents of C. sativa, such as cannabidiol, for
potential therapeutic use. In this issue of the British Journal of
Pharmacology, De Petrocellis and colleagues present comprehensive evidence that
plant-derived cannabinoids, especially cannabidiol, are potent inhibitors of
prostate carcinoma viability in vitro. They also showed that the extract was
active in vivo, either alone or when administered with drugs commonly used to
treat prostate cancer (the anti-mitotic chemotherapeutic drug docetaxel
(Taxotere) or the anti-androgen bicalutamide (Casodex)) and explored the
potential mechanisms behind these antineoplastic effects.
In Vitro Anticancer Activity of Plant-Derived
Cannabidiol on Prostate Cancer Cell Lines
Cannabinoids, the active components of Cannabis sativa Linnaeus,
have received renewed interest in recent years due to their diverse
pharmacologic activities such as cell growth inhibition, anti-inflammatory
effects and tumor regression, but their use in chemotherapy is limited by their
psychotropic activity. To date, cannabinoids have been successfully used in the
treatment of nausea and vomiting, two common side effects that accompany
chemotherapy in cancer patients. Most non-THC plant cannabinoids e.g.
cannabidiol and cannabigerol, seem to be devoid of psychotropic properties.
However, the precise pathways through which these molecules produce an
antitumor effect have not yet been fully characterized. We therefore
investigated the antitumor and anti-inflammatory activities of cannabidiol
(CBD) in human prostate cancer cell lines LNCaP, DU145, PC3, and assessed
whether there is any advantage in using cannabis extracts enriched in
cannabidiol and low in THC. Results obtained in a panel of prostate cancer cell
lines clearly indicate that cannabidiol is a potent inhibitor of cancer cell growth,
with significantly lower potency in non-cancer cells. The mRNA expression level
of cannabinoid receptors CB1 and CB2, vascular
endothelial growth factor (VEGF), PSA (prostate specific antigen) are
significantly higher in human prostate cell lines. Treatment with Cannabis
extract containing high CBD down regulates CB1, CB2, VEGF, PSA,
pro-inflammatory cytokines/chemokine IL-6/IL-8. Our overall findings support
the concept that cannabidiol, which lacks psychotropic activity, may possess
anti-inflammatory property and down regulates both cannabinoid receptors, PSA,
VEGF, IL-6 and IL-8. High CBD cannabis extracts are cytotoxic to androgen
responsive LNCaP cells and may effectively inhibit spheroid formation in cancer
stem cells. This activity may contribute to its anticancer and chemosensitizing
effect against prostate cancer. Cannabidiol and other non-habit forming
cannabinoids could be used as novel therapeutic agents for the treatment of
prostate cancer.
Induction of apoptosis by cannabinoids in prostate and
colon cancer cells is phosphatase dependent.
We hypothesized that the anticancer activity of cannabinoids
was linked to induction of phosphatases.
The effects of cannabidiol (CBD) and the synthetic
cannabinoid WIN-55,212 (WIN) on LNCaP (prostate) and SW480 (colon) cancer cell
proliferation were determined by cell counting; apoptosis was determined by
cleavage of poly(ADP)ribose polymerase (PARP) and caspase-3 (Western blots);
and phosphatase mRNAs were determined by real-time PCR. The role of
phosphatases and cannabinoid receptors in mediating CBD- and WIN-induced
apoptosis was determined by inhibition and receptor knockdown.
CBD and WIN inhibited LNCaP and SW480 cell growth and
induced mRNA expression of several phosphatases, and the phosphatase inhibitor
sodium orthovanadate significantly inhibited cannabinoid-induced PARP cleavage
in both cell lines, whereas only CBD-induced apoptosis was CB1 and CB2
receptor-dependent.
Cannabinoid receptor agonists induce phosphatases and
phosphatase-dependent apoptosis in cancer cell lines; however, the role of the
CB receptor in mediating this response is ligand-dependent.
SKIN CANCER
Anticancer activity of anandamide in human cutaneous
melanoma cells.
Cannabinoids are implicated in the control of cell
proliferation, but little is known about the role of the endocannabinoid system
in human malignant melanoma. This study was aimed at characterizing the in
vitro antitumor activity of anandamide (AEA) in A375 melanoma cells. The mRNA
expression of genes that code for proteins involved in the metabolism and in
the mechanism of AEA action was assessed by RT-PCR. Cell viability was tested
using WST-1 assay and the apoptotic cell death was determined by measuring
caspase 3/7 activities. A375 cells express high levels of fatty acid amide
hydrolase (FAAH), cyclooxygenase (COX)-2, cannabinoid receptor 1 (CB1),
transient receptor potential cation channel subfamily V member 1 (TRPV1) and
G-protein-coupled receptor 55 (GPR55) genes. AEA induced a
concentration-dependent cytotoxicity with an IC50 of 5.8 ± 0.7 µM and such an
effect was associated to a caspase-dependent apoptotic pathway. AEA
cytotoxicity was potentiated by FAAH inhibition (2-fold increase, p<0.05)
and mitigated by COX-2 or lipoxygenase (LOX) inhibition (5- and 3-fold
decrease, respectively; p<0.01). Blocking CB1 receptors partially decreased
AEA cytotoxicity, whereas selective antagonism on the TRPV1 barely affected the
mechanism of AEA action. Finally, methyl-β-cyclodextrin, a membrane cholesterol
depletory, completely reversed the cytotoxicity induced by the selective GPR55
agonist, O-1602, and AEA. Overall, these findings demonstrate that AEA induces
cytotoxicity against human melanoma cells in the micromolar range of
concentrations through a complex mechanism, which involves COX-2 and
LOX-derived product synthesis and CB1 activation. Lipid raft modulation,
probably linked to GPR55 activation, might also have a role.
Are You Curious About Using Cannabis for Cancer?
In the meantime, if you are on a cancer-healing path and
are considering using cannabinoids, here are some general guidelines that
experts agree are worth considering:
- Do your own research. The best way to learn about the power of cannabis in healing cancer is to start digging. There are approximately 500 articles on Pubmed alone relating to cannabis and cancer. Learn about strains, qualified targeted research studies, what method of administration may be right for you, and the importance of balancing the Endocannabinoid System.
- Know your source. Unfortunately, because the medical cannabis industry is largely unregulated, charlatans selling bogus products definitely exist. You should not have to pay exorbitant amounts of money for any cannabis product that you buy from regulated pharmacies or online. Also, make quality a priority for you. Be sure that your product comes from an organic source and that you know that the plant has not been grown or processed using pesticides.
- Stick with natural cannabis products. Synthetically-produced cannabinoids such as Marinol are commercially available. However, anecdotal evidence has found that these do not work as efficiently as natural substances do.
- Work with a professional healthcare provider trained in cannabinoid therapy. These professionals are out there in increasing numbers, especially in states where the medical cannabis industry is well established or growing, such as California and Colorado. Reach out to a patient advocate group online if no qualified professionals are in your area.
- Make cannabis therapy an important part of your overall cancer-healing toolbox. A well-rounded naturally-based cancer healing protocol involves working with the body’s own healing mechanisms through a variety of means. For you, this may mean changes to your diet and lifestyle, reducing stress, getting quality sleep, moving your body, intense detoxing protocols, and using other supplements and proven natural methods in addition to the powerful healing power of cannabis.
Thetruthaboutcancer.org for more info go to: https://thetruthaboutcancer.com/cannabis-and-cancer/
Which Cannabis Treatments are Helpful for Cancer?
Unfortunately for many cannabis lovers out there, smoking
the herb is NOT an effective treatment for cancer. Neither is eating the
occasional infused-brownie or lemonade. In fact, cannabis is not an approved
cancer treatment in the majority of countries.
Yet, medical cannabis patients hoping to reap the most
benefit from the plant utilize the herb in several different ways. While it’s
vital to work with a canna-savvy medical professional before changing your
treatment plan, here are some common ways cancer patients use the herb:
1. Full-extract medical cannabis oil
Medical cannabis patients hoping to incorporate the plant
into their cancer routine often rely on full extract medical cannabis
oil. Sometimes referred to as Rick Simpson Oil (RSO), medical cannabis oil
is the concentrated essential oil of the cannabis plant.
This oil is often extracted from large quantities of
cannabis using a grain alcohol or ethanol as a solvent. The solvent is burned
off through the extraction process. This oil is perhaps the most powerful
cannabis product available. Cannabis patients often take this oil both
topically and orally, depending on the circumstances.
To learn more about medical cannabis oil, check out these
three articles:
- Cannabis Oil: One Of The Most Potent Products Around
- How to Make The Best Medical Cannabis Oil
- How to Pick The Best Medical Cannabis Oil
2. Edibles
Edibles are a popular choice for strong symptom management,
especially pain. Cannabis-infused foods provide a more powerful experience than
simply inhaling the herb. Teas, tinctures,
and baked goods are some of the most common forms of edible cannabis.
When consuming oral cannabis, the effects of the herb can
take significantly longer to take effect. Expect to wait 30 minutes to two
hours before relief.
3. Raw dietary cannabis
Believe it or not, raw cannabis is not psychoactive. Here, “raw”
refers to fresh plant material that has not been dried or heated. While there
is no significant research on dietary cannabis and cancer, many patients choose
to incorporate raw cannabis juices, smoothies, and foodstuffs into their
routines.
Very early evidence suggests that some of the acids present in
raw cannabis, notably the precursor acids to THC and CBD (THCA and CBDA), have
demonstrated anticancer
effects. However, raw cannabis alone certainly won’t cure the disease.
Instead, dietary cannabis is more like a superfood that promotes good health.
For more information on raw dietary cannabis, read the full
article here.
Want to find people or groups who are also fighting
cancer with cannabis?
You could get support, help, more information, or possibly find some local people who have been doing the same things you are about to embark in. I find groups to be supportive. Here is a small list of Cannabis and Cancer Groups I found on Facebook:
Resources:
http://wondergressive.com/cannabis-cures-cancer-review-evidence/#6_Cannabis_Cures_Cancer
https://www.thedailybeast.com/marijuana-fights-cancer-and-helps-manage-side-effects-researchers-find