Long used to treat depression, selective serotonin reuptake inhibitors (SSRIs) could help improve modern cancer treatments.
In mouse experiments, they slowed the growth of pancreatic and colon cancers, and when combined with immunotherapy, they even halted cancer growth long-term. In some cases the tumours disappeared completely. The researchers’ findings will now be tested in human clinical trials.
The neurotransmitter serotonin, known as the happiness molecule, has many other functions and is mostly found outside the brain, stored in blood platelets. Serotonin reuptake inhibitors (SSRIs), which are used to treat depression, increase serotonin levels in the brain but reduce serotonin in platelets.
Serotonin was already known to be involved in carcinogenesis. Until now, however, the underlying mechanisms had remained obscure. Now, researchers at the University of Zurich (UZH) and University Hospital Zurich (USZ) have shown that SSRIs or other drugs that lower peripheral serotonin levels can also slow cancer growth in mice.
Pierre-Alain Clavien, Director, Department of Surgery and Transplantation, University of Zurich, said: “Drugs that are already approved for clinical use as antidepressants could help improve treatment of hitherto incurable pancreatic and colorectal cancers.”
Although recent years have seen new, effective treatments such as targeted antibodies or immunotherapies, most patients with advanced-stage abdominal tumours such as colon or pancreatic cancer die within a few years of diagnosis. Tumour cells eventually become resistant to the drugs and are no longer recognised by the immune system. Now, the researchers have discovered the role serotonin plays in this tumour cell resistance mechanism.
Cancer cells use serotonin to boost production of an immunoinhibitory molecule, PD-L1, which binds to killer T cells, rendering them dysfunctional. The cancer cells thus escape destruction by the immune system. In mouse models, the researchers were able to show that SSRIs or peripheral serotonin synthesis inhibitors prevent this mechanism. “This class of antidepressants and other serotonin blockers cause immune cells to recognise and efficiently eliminate tumor cells again. This slowed the growth of colon and pancreatic cancers in the mice,” Clavien said.
PD-L1, via which serotonin exerts its effect, is also the target of modern immunotherapies, also called immune checkpoint inhibitors. The researchers then tested a dual treatment approach in mice: immunotherapy, which increases the activity of killer T cells, was combined with drugs that reduce peripheral serotonin. Cancer growth was suppressed in the animal models in the long term, and in some mice, the tumours disappeared completely.
“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,” said Clavien.
Source: University of Zurich
