Cancer Growth inhibition by Antidepressant Sertraline

Mouse experiments by KU Leuven researchers have shown how the antidepressant sertraline can help inhibit cancer cell growth by acting on metabolic addiction to the amino acids serine and glycine, which certain forms of cancers produce to make them thrive. The researchers suggest the findings may point to a new therapeutic approach to cancer care.

Kim De Keersmaecker, PhD, head of the Laboratory for Disease Mechanisms in Cancer (LDMC), said This mechanism is an interesting target because cancer cells are so dependent on it." To a lesser degree, healthy cells use this process and often take up serine and glycine from food. For cancer cells, however this is not enough, meaning they are beginning to develop more. We would be able to combat cancer without affecting healthy cells if we can stop this production.

These results were reported in Molecular Cancer Therapeutics, under titled, “Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis addicted breast tumor growth."

Energy metabolism rewiring is one of the hallmarks of cancer that promotes tumour growth, survival, and chemotherapy resistance, the authors explained. Normal cells may rely on the uptake from their environment of the amino acids serine and glycine, but malignant cells also produce large amounts of these amino acids in some types of cancer, including breast, leukaemia, skin, brain, lung, and others. This serine and glycine development promotes cancer cell growth to such an extent that they become addicted effectively.

"In cancer subsets, including triple-negative breast cancer and T-cell leukaemia that are both currently treated with toxic intensive chemotherapy regimens, evidence of dependence on serine/glycine synthesis is increasing," the authors noted. "This highlights the need to develop novel therapeutic intervention strategies for these cancers, focusing specifically on serine/glycine synthesis targeting."

The researchers used a database of existing medicines in their hunt for a material that affects the synthesis of serine and glycine. Researchers in the laboratory of Bruno Cammue, PhD, at the Centre for Microbial and Plant Genetics (CMPG), examined 1,600 substances on yeast cells for the first step of their studies. Because there are also yeasts or moulds that rely on the same mechanism," explained Karin Thevissen, PhD, research coordinator." "These amino acids are developed by certain yeasts to defend themselves against antifungals. Moreover, you can grow yeast cells quickly allowing you to test several different substances.

The screening results showed that the antidepressant sertraline was the most effective substance in blocking the production of serine and glycine, with further tests showing that the drug inhibits the enzyme SHMT for serine/glycine synthesis. A combination of sertraline and the antimalarial medication artemether, which had been previously shown to have potent anticancer efficacy, resulted in sertraline-selective antitumor activity when tested in mice carrying breast cancer xenografts.

Shauni Geeraerts, PhD, at LDMC and CMPG, and LDMC colleague Kim Kampen, PhD, commented that other studies had already suggested that sertraline had a certain anticancer effect, but there was no reason for this yet. We have been able to demonstrate in this study that sertraline inhibits serine and glycine production, causing cancer cell growth to decline. We have found that in combination with other therapeutic agents, this drug is the most effective. We observed in experiments with mice that sertraline significantly inhibits the growth of breast cancer cells in conjunction with another treatment.

The team said their findings suggest that it could be possible to repurpose sertraline as a candidate for anticancer. "In conclusion, the widely used antidepressant sertraline was identified as a novel serine/glycine synthesis enzyme SHMT inhibitor that showed high efficacy against cancers that are metabolically addicted," they wrote. And although serine/glycine synthesis enzyme inhibitors previously described have not entered clinical trials, sertraline is already being safely used in humans, they pointed out. Our findings indicate that sertraline may be used as an adjuvant therapeutic intervention strategy for serine/glycine synthesis of addicted cancers, especially when combined with drugs that target other central cancer cell metabolism nodes, such as mitochondrial inhibitors. This research collectively offers molecular insights into the repurposed mode of action of the sertraline antidepressant and allows for the delineation of a previously undisclosed community of cancers that are especially susceptible to sertraline care.

"We can begin examining other types of cancer that are also addicted to serine and glycine synthesis now that we have been able to identify this mechanism for breast cancer," said Professor De Keersmaecker. This is the case with T-cell leukaemia, for example, but also with some types of cancers of the brain, lungs and skin. The more sertraline-sensitive tumours we can discover, the better the chances for treating patients in the future... These are of course, preliminary research findings, not clinical trials, so we can be hopeful about the possibilities. The protection of human use of sertraline has already been well described, which is a major gain. That's why we are also looking for industrial partners to expand this further.