丝氨酸
药理学
丝氨酸羟甲基转移酶
甘氨酸
生物化学
药物重新定位
舍曲林
化学
生物
抗抑郁药
酶
药品
氨基酸
内分泌学
海马体
作者
Shauni Lien Geeraerts,Kim R. Kampen,Gianmarco Rinaldi,Purvi Gupta,Mélanie Planque,Nikolaos Louros,Elien Heylen,Kaat De Cremer,Katrijn De Brucker,Stijn Vereecke,Benno Verbelen,Pieter Vermeersch,Joost Schymkowitz,Frédéric Rousseau,David Cassiman,Sarah‐Maria Fendt,Arnout Voet,Bruno P.A. Cammue,Karin Thevissen,Kim De Keersmaecker
标识
DOI:10.1158/1535-7163.mct-20-0480
摘要
Abstract Metabolic rewiring is a hallmark of cancer that supports tumor growth, survival, and chemotherapy resistance. Although normal cells often rely on extracellular serine and glycine supply, a significant subset of cancers becomes addicted to intracellular serine/glycine synthesis, offering an attractive drug target. Previously developed inhibitors of serine/glycine synthesis enzymes did not reach clinical trials due to unfavorable pharmacokinetic profiles, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. In this study, we aimed to develop therapies that can rapidly enter the clinical practice by focusing on drug repurposing, as their safety and cost-effectiveness have been optimized before. Using a yeast model system, we repurposed two compounds, sertraline and thimerosal, for their selective toxicity against serine/glycine synthesis–addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines. Isotope tracer metabolomics, computational docking, enzymatic assays, and drug–target interaction studies revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase and phosphoglycerate dehydrogenase, respectively. In addition, we demonstrated that sertraline's antiproliferative activity was further aggravated by mitochondrial inhibitors, such as the antimalarial artemether, by causing G1–S cell-cycle arrest. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts. 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. Furthermore, we highlight the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a novel treatment strategy for serine/glycine synthesis–addicted cancers.
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