Released: Mon 28-Jul-2008, 16:55 ET Embargo expired: Fri 01-Aug-2008, 00:05 ET Turned-off Cannabinoid Receptor Turns on Colorectal Tumor CANNABINOID, COLORECTAL CANCER,DUBOIS, CB1, RECEPTOR, DECITABINE, M. D.
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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.
Newswise — New preclinical research shows thatcannabinoid cell surface receptor CB1 plays a tumor- suppressing role in human colorectal cancer, scientistsreport in the Aug. 1 edition of the journal CancerResearch.
CB1 is well-established for relieving pain and nausea,elevating mood and stimulating appetite by serving asa docking station for the cannabinoid group ofsignaling molecules. It now may serve as a new pathfor cancer prevention or treatment.
"We've found that CB1 expression is lost in mostcolorectal cancers, and when that happens a cancer-promoting protein is free to inhibit cell death," saidsenior author Raymond DuBois, M.D., Ph.D., provostand executive vice president of The University ofTexas M. D. Anderson Cancer Center.
DuBois and collaborators from Vanderbilt-Ingram Raymond DuBois, M.D., Ph.D. Provost and Executive Cancer Center also show that CB1 expression can be Vice President at M. D. Anderson Cancer Center.
restored with an existing drug, decitabine. They foundthat mice prone to developing intestinal tumors thatalso have functioning CB1 receptors develop fewerand smaller tumors when treated with a drug thatmimics a cannabinoid receptor ligand. Ligands aremolecules that function by binding to specific Click image to view fullsize receptors. Agonists are synthetic molecules that mimic

the action of a natural molecule.
"Potential application of cannabinoids as anti-tumordrugs is an exciting prospect, because cannabinoidagonists 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 cancertreatment or prevention." Cannabinoids are a group of ligands that serve a variety of cell-signaling roles. Some are produced by the bodyinternally (endocannabinoids). External cannabinoids include manmade versions and those present in plants, mostfamously 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 toprotect the colon against inflammation. Since chronic inflammation is a known risk factor for colorectal cancer, theresearchers 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. "Themolecular 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 colorectalcancer cell lines. Further experimentation showed that the gene that encodes the CB1 protein was not damaged, butshut down chemically by the attachment of methyl groups - a carbon atom surrounded by three hydrogen atoms - tothe gene encoding CB1.
Treating cell lines with decitabine, a demethylating agent approved for some types of leukemia, removed the methylgroups, 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 precancerouspolyps resulted in a 2.5-to-3.8-fold increase in the number of polyps and a 10-fold increase in the number of largegrowths, 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 from16.7 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 - programmedcell death. The team confirmed the role of CB1 in apoptosis, showing that tumor cells with high CB1 expression weresensitive 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 isoverexpressed in nearly every human tumor but is barely detectable in normal tissue, DuBois noted. Overexpression ofsurvivin is associated with poor outcome and reduced apoptosis in colorectal cancer patients. The researcherspinpointed 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 thetumor 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. Furtherinvestigation, the researchers note, is needed to define its role in those diseases and other types of cancer. The teamalso 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. Micewith CB1 blocked in this manner also showed an increase in the number and size of polyps. A CB1 antagonist calledrimonabant is currently marketed overseas for weight loss. The researchers note that a patient's risk for colorectalcancer 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 ResearchAlliance.
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.
About M. D. AndersonThe University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centersfocused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 39 ComprehensiveCancer Centers designated by the National Cancer Institute. For five of the past eight years, M. D. Anderson hasranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and WorldReport.
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