Studies in mice by investigators at the KU Leuven have demonstrated how the antidepressant sertraline can help to inhibit the growth of cancer cells, by acting on a metabolic addiction to the amino acids serine and glycine, which some types of cancers develop to allow them to thrive. The researchers say the results might point to new therapeutic approach to treating cancer.
“This mechanism is an interesting target because cancer cells are so dependent on it”, said Kim De Keersmaecker, PhD, head of the Laboratory for Disease Mechanisms in Cancer (LDMC). “Healthy cells use this mechanism to a lesser extent and also take up serine and glycine from food. This is not sufficient for cancer cells, however, meaning they start producing more. If we can halt this production, we will be able to fight the cancer without affecting healthy cells.”
The researchers findings are reported in Molecular Cancer Therapeutics, in a paper titled, “Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis addicted breast tumor growth.”
Rewiring of energy metabolism is one of the hallmarks of cancer that supports tumor growth, survival, and resistance to chemotherapy, the authors explained. Normal cells can rely on uptake of the amino acids serine and glycine from their environment, but in certain types of cancer—including breast, leukemia, skin, brain, lung, and others—the malignant cells also produce large amounts of these amino acids. This production of serine and glycine stimulates the growth of cancer cells to such an extent that they effectively become addicted.
“Evidence for dependency on serine/glycine synthesis in cancer subsets, including triple-negative breast cancer and T-cell leukemia that are both currently treated with toxic intensive chemotherapy regimens, is growing,” the authors noted. “This highlights the necessity to develop novel therapeutic intervention strategies for these cancers, specifically focusing on targeting serine/glycine synthesis.”
In their search for a substance that influences the synthesis of serine and glycine, the researchers utilized a database of existing medicines. For the first phase of their studies, researchers in the lab of Bruno Cammue, PhD, at the Centre for Microbial and Plant Genetics (CMPG), tested 1,600 substances on yeast cells. “Because there are also yeasts, or moulds, which depend on the same mechanism”, explained research coordinator Karin Thevissen, PhD. “Certain yeasts produce these amino acids to protect themselves against antifungals. In addition, you can easily grow yeast cells, allowing you to test many different substances.”
The screening results indicated that the antidepressant sertraline was the most effective substance at blocking serine and glycine production, with further experiments demonstrating that the drug inhibits the serine/glycine synthesis enzyme SHMT. When tested in mice carrying breast cancer xenografts, a combination of sertraline and the antimalarial drug artemether—which had previously been shown to have potent anticancer activity—resulted in sertraline-selective antitumor activity.
“Other studies had already indicated that sertraline has a certain anticancer activity, but there was no explanation for this yet”, commented Shauni Geeraerts, PhD, at the LDMC and CMPG, and LDMC colleague Kim Kampen, PhD. “In this study, we’ve been able to demonstrate that sertraline inhibits the production of serine and glycine, causing decreased growth of cancer cells. We also found that this substance is most effective in combination with other therapeutic agents. In studies with mice we saw that sertraline in combination with another therapy strongly inhibits the growth of breast cancer cells.”
The team said that their results indicate it may be possible to repurpose sertraline as an anticancer candidate. “In conclusion, we identified the widely used antidepressant sertraline as a novel inhibitor of serine/glycine synthesis enzyme SHMT that demonstrated high efficacy against metabolically addicted cancers,” they wrote. And while previously identified inhibitors of serine/glycine synthesis enzymes haven’t reached clinical trials, sertraline is already being used safely in humans, they pointed out. “Our results suggest that sertraline may have applications as adjuvant therapeutic intervention strategy for serine/glycine synthesis addicted cancers, especially when combined with drugs attacking other central nodes of cancer cell metabolism such as mitochondrial inhibitors … Collectively, this study provides molecular insights into the repurposed mode-of-action of the antidepressant sertraline and allows to delineate a hitherto unidentified group of cancers being particularly sensitive to treatment with sertraline…”
“Now that we’ve been able to identify this mechanism for breast cancer, we can start examining other types of cancer that are also addicted to serine and glycine synthesis”, said professor De Keersmaecker. “This is for example the case in T-cell leukemia, but also in certain types of brain, lung and skin cancer. The more tumors we can identify that are sensitive to sertraline, the better the prospects are for helping patients in the future … These are, of course, results of experimental research, not clinical studies, but we can be optimistic about the potential. The safety of using sertraline in humans has already been well described, which is a great advantage. That’s why we are also looking for industrial partners to develop this further.”