Study published in Cancer Research shows that when CB1 expression is lost, a cancer-promoting protein is free to inhibit cell death.
Cannabinoid cell surface receptor CB1 plays a tumor-suppressing role in colorectal cancer, report scientists at The University of Texas M. D. Anderson Cancer Center and Vanderbilt-Ingram Cancer Center.
“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,” explains senior author Raymond DuBois, M.D., Ph.D., provost and evp of M. D. Anderson Cancer Center.
The team also showed that CB1 expression can be restored with an existing drug, decitabine. Additionally, 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, according to the researchers.
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.
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.
Treating cell lines with decitabine, a demethylating agent approved for some types of leukemia, removed the methyl groups, restoring gene expression in seven of eight 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% to 50%. The reduction was greater for larger polyps.
“Just increasing the levels of cannabinoids to treat colorectal cancer won’t work if the CB1 receptor is not present,” Dr. DuBois asserts. 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.
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 results appear in August 1 edition of Cancer Research.
