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Science Forum Index » Medicine - Cancer Forum » Activation of cannaboid receptor plus cannaboid...
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| Steve... |
 Posted: Sun Aug 03, 2008 12:04 am |
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This apparently is working (according to the article below) by inhibiting
the protein survivin in cancer cells. There are other agents that inhibit
survivin as well such as DHA (omega 3 fatty acid), lipoic acid, resveratrol,
selenium, silymarin, sulindac, vitamin D3, vitamin A, and Zyflamend.
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http://www.eurekalert.org/bysubject/medicine.php
Public release date: 1-Aug-2008
University of Texas M. D. Anderson Cancer Center
Turned-off cannabinoid receptor turns on colorectal tumor growth
HOUSTON - New preclinical research shows that cannabinoid cell surface
receptor CB1 plays a tumor-suppressing role in human colorectal cancer,
scientists report in the Aug. 1 edition of the journal Cancer Research.
CB1 is well-established for relieving pain and nausea, elevating mood and
stimulating appetite by serving as a docking station for the cannabinoid
group of signaling molecules. It now may serve as a new path for cancer
prevention or treatment.
"We've found that CB1 expression is lost in most colorectal cancers, and
when that happens a cancer-promoting protein is free to inhibit cell death,"
said senior author Raymond DuBois, M.D., Ph.D., provost and executive vice
president of The University of Texas M. D. Anderson Cancer Center.
DuBois and collaborators from Vanderbilt-Ingram Cancer Center also show that
CB1 expression can be restored with an existing drug, decitabine. They found
that mice prone to developing intestinal tumors that also have functioning
CB1 receptors develop fewer and smaller tumors when treated with a drug that
mimics a cannabinoid receptor ligand. Ligands are molecules that function by
binding to specific receptors. Agonists are synthetic molecules that mimic
the action of a natural molecule.
"Potential application of cannabinoids as anti-tumor drugs is an exciting
prospect, because cannabinoid agonists are being evaluated now to treat the
side-effects of chemotherapy and radiation therapy," DuBois said. "Turning
CB1 back on and then treating with a cannabinoid agonist could provide a new
approach to colorectal cancer treatment or prevention."
Cannabinoids are a group of ligands that serve a variety of cell-signaling
roles. Some are produced by the body internally (endocannabinoids). External
cannabinoids include manmade versions and those present in plants, most
famously the active ingredient in marijuana (THC).
Receptor shutdown by methylation
Endocannabinoid signaling is important to the normal functioning of the
digestive system and has been shown to protect the colon against
inflammation. Since chronic inflammation is a known risk factor for
colorectal cancer, the researchers decided to look into the role of
cannabinoid receptors in a mouse model of colon cancer.
"People have looked at cannabinoids in cancer earlier, mainly in cell
culture experiments," DuBois said. "The molecular mechanisms for loss of the
receptor and its effect on cancer have not been previously shown."
First, the team found that CB1 was largely absent in 18 of 19 human tumor
specimens and in 9 of 10 colorectal cancer cell lines. Further
experimentation showed that the gene that encodes the CB1 protein was not
damaged, but shut down chemically by the attachment of methyl groups - a
carbon atom surrounded by three hydrogen atoms - to the gene encoding CB1.
Treating cell lines with decitabine, a demethylating agent approved for some
types of leukemia, removed the methyl groups, restoring gene expression in 7
of 8 cell lines and full expression of CB1 protein in three lines.
Next, the group found that deletion of the CB1 gene in a strain of mice that
spontaneously develops precancerous polyps resulted in a 2.5-to-3.8-fold
increase in the number of polyps and a 10-fold increase in the number of
large growths, those most likely to develop into cancer.
Treating mice that had the CB1 receptor with an endocannabinoid agonist
resulted in a decline in polyps ranging from 16.7 percent to 50 percent. The
reduction was greater for larger polyps.
CB1 thwarts survivin, a protein that protects cancer
Cannabinoids previously had been shown to kill cancer cells in lab
experiments by inducing apoptosis - programmed cell death. The team
confirmed the role of CB1 in apoptosis, showing that tumor cells with high
CB1 expression were sensitive to apoptosis when treated by a cannabinoid
agonist. Cell lines with silenced CB1 resisted cell death.
A series of experiments showed that CB1 increases cancer cell death by
stifling a protein called survivin. Survivin is overexpressed in nearly
every human tumor but is barely detectable in normal tissue, DuBois noted.
Overexpression of survivin is associated with poor outcome and reduced
apoptosis in colorectal cancer patients. The researchers pinpointed a cell
signaling pathway by which activated CB1 cuts down survivin.
"Just increasing the levels of cannabinoids to treat colorectal cancer won't
work if the CB1 receptor is not present," DuBois said. This suggests that
treating first with a demethylating agent, such as decitabine, to reactivate
CB1 in the tumor and following up with a cannabinoid might be an effective
attack on colorectal cancer.
Scarcity of CB1 also is associated with Huntington's disease, Alzheimer's
disease and multiple sclerosis. Further investigation, the researchers note,
is needed to define its role in those diseases and other types of cancer.
The team also analyzed the other main cannabinoid receptor, CB2, and found
no role for it in colorectal cancer.
They also treated the mice with a CB1 antagonist, a compound that binds to
the receptor but does not activate it. Mice with CB1 blocked in this manner
also showed an increase in the number and size of polyps. A CB1 antagonist
called rimonabant is currently marketed overseas for weight loss. The
researchers note that a patient's risk for colorectal cancer should be
assessed when use of such drugs is being considered.
###
The study was funded by grants from the National Cancer Institute and the
National Colorectal Cancer Research Alliance.
Co-authors with DuBois are first author Dingzhi Wang, Ph.D., Haibin Wang,
Ph.D., Wei Ning, Michael Backlund, Ph.D., and Dushansu K. Dey, Ph.D., all of
the Vanderbilt-Ingram Cancer Center. |
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