Scientists from a recent study had discovered that commonly prescribed anti-depressant drugs can halt growth of cancer cells in mice.
When combined with immunotherapy, these medication increases survival rates of rodents suffering from pancreatic and colon cancers, and even capable of ‘completely’ eliminating tumor growth in up to a third of cases.
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MIAMI, FL – MARCH 23: A bottle of antidepressant pills named Effexor is shown March 23, 2004 photographed in Miami, Florida. The Food and Drug Administration asked makers of popular antidepressants to add or strengthen suicide-related warnings on their labels as well as the possibility of worsening depression especially at the beginning of treatment or when the doses are increased or decreased.
There had been previous studies that shows how peripheral serotonin in the blood assists tumor cells to avoid recognition by immune system, thus playing a role in cell proliferation and cancer. However, the mechanism behind this effect has been unexplored.
The study authors dive into determining what role exactly does neurotransmitter serotonin play in cancer development.
Suppressing serotonin to enhance immunotherapy
Here, the team used syngeneic mouse models of pancreatic and colorectal cancer in mice, genetically engineered to lack peripheral serotonin, and found that its genetic knockdown reduces tumor growth, compared to regular rodents with similar illness. A more detailed analysis shows that tumors of serotonin-deficient mice have accumulated higher concentrations of enhanced immune cells called CD8+ T cell or killer T cells, that destroys the tumor itself.
“In addition, the pharmacological serotonin inhibitors fluoxetine and telotristat were able to enhance the effects of anti-PD-1 therapy to induce long-term tumor control in mice,” authors wrote on their work published in the journal Science Translational Medicine.
“These FDA-approved drugs suggest a promising combination treatment to improve cancer immunotherapy that warrants further clinical investigation,” they added.
Moreover, the tumors in engineered mice contained lower levels of PD-L1, an immunoinhibitory molecule that blocks killer T cells. Cancer immunotherapies find it wise to focus on restraining PD-L1 for that reason.
In conclusion, as peripheral serotonin enhances PD-L1 in cancer cells, the tumor grows. That is why anti-depressant drugs like selective serotonin reuptake inhibitors (SSRIs) work by increasing serotonin levels in the brain but decreasing peripheral serotonin in blood platelets. The study authors suggests that these medications may help reduce PD-L1 in cancer cells.
Without serotonin, the cancer cells are no longer recognized by the immune system
When common SSRI called fluoxetine was combined with anti-PD-L1 immunotherapy, proliferation of cancer cells has been curbed and enhanced survival rate sick mice. There was significant increase in killer T cell concentrations within tumors, “enabling eradication of large established tumors in 20 percent of mice.”
In spite having other effective treatments for several years, most patients with advanced-stage abdominal tumors such as colon or pancreatic cancer die within a few years of diagnosis, as tumor cells become resistant to the drugs over time.
“This class of antidepressants and other serotonin blockers cause immune cells to recognize and efficiently eliminate tumor cells again. This slowed the growth of colon and pancreatic cancers in the mice,” says Pierre-Alain Clavien, director of the Department of Surgery and Transplantation.
“Our results provide hope for cancer patients, as the drugs used are already approved for clinical use. Testing such drug combinations on cancer patients in clinical trials can be fast-forwarded due to the known safety and efficacy of the drugs.”
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