Antidepressants found to inhibit tumour growth in mice
Classic antidepressants have been found to slow the growth of pancreatic and colon cancers in mice, according to researchers at the University of Zurich (UZH) and University Hospital Zurich (USZ). When combined with immunotherapy the drugs managed to stop the cancer growth long term, and in some cases the tumours disappeared completely.
Serotonin is a neurotransmitter that is also known as the happiness hormone because of its beneficial effects on mood. In depressed people, the concentration of serotonin in the brain is reduced. The hormone also influences many other functions throughout the body; indeed, the majority of the serotonin is not located in the brain, but is stored in the blood platelets. Serotonin reuptake inhibitors (SSRIs), which are used to treat depression, increase serotonin levels in the brain but decrease peripheral serotonin in platelets.
The involvement of serotonin in carcinogenesis was already known, but until now the underlying mechanisms had remained obscure. Now, researchers led by Pierre-Alain Clavien and Anurag Gupta have discovered the role serotonin plays in tumour cell resistance — in which tumour cells become resistant to treatment over time and are no longer recognised by the immune system — and shown how SSRIs and other drugs that lower peripheral serotonin levels can also slow cancer growth.
Cancer cells use serotonin to boost the production of a molecule that is immunoinhibitory, known as PD-L1. This molecule binds to killer T cells, a specific type of immune cell that recognises and eliminates tumour cells, and renders them dysfunctional. The cancer cells thus avoid being destroyed by the immune system. In experiments with mice, 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 tumour cells again,” Clavien said. “This slowed the growth of colon and pancreatic cancers in the mice.”
PD-L1, through which serotonin exerts its effect, is also the target of modern immunotherapies known as immune checkpoint inhibitors. The researchers next tested a dual treatment approach in mice: they combined immunotherapy, which increases the activity of killer T cells, 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.
The team’s findings, published in the journal Science Translational Medicine, will now be tested in human clinical trials — a process that can be streamlined as the drugs used are already approved for clinical use, Clavien noted.
“Testing such drug combinations on cancer patients in clinical trials can be fast-forwarded due to the known safety and efficacy of the drugs,” he said.
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