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.

中文翻译：

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将抗抑郁药舍曲林重新用作 SHMT 抑制剂以抑制丝氨酸/甘氨酸合成成瘾的乳腺肿瘤生长。

代谢重组是癌症的标志，支持肿瘤生长、存活和化疗耐药。尽管正常细胞通常依赖细胞外丝氨酸和甘氨酸供应，但相当一部分癌症对细胞内丝氨酸/甘氨酸合成上瘾，从而提供了一个有吸引力的药物靶点。由于不利的药代动力学特征，先前开发的丝氨酸/甘氨酸合成酶抑制剂没有进入临床试验，这意味着需要进一步努力确定针对该途径的临床适用药物。在这项研究中，我们的目标是通过专注于药物再利用来开发可以快速进入临床实践的疗法，因为它们的安全性和成本效益之前已经过优化。使用酵母模型系统，我们重新利用了两种化合物，舍曲林和硫柳汞，对丝氨酸/甘氨酸合成成瘾的乳腺癌和 T 细胞急性淋巴细胞白血病细胞系的选择性毒性。同位素示踪代谢组学、计算对接、酶分析和药物-靶标相互作用研究表明，舍曲林和硫柳汞分别抑制丝氨酸/甘氨酸合成酶丝氨酸羟甲基转移酶和磷酸甘油酸脱氢酶。此外，我们证明了通过引起 G1-S 细胞周期停滞，线粒体抑制剂（如抗疟蒿甲醚）进一步加剧了舍曲林的抗增殖活性。最值得注意的是，这种组合还在乳腺癌小鼠异种移植物中产生了丝氨酸选择性抗肿瘤活性。总的来说，这项研究提供了对抗抑郁药舍曲林重新利用的作用方式的分子见解，并允许描绘出一组迄今为止对舍曲林治疗特别敏感的未鉴定癌症。此外，我们强调同时抑制丝氨酸/甘氨酸合成和线粒体代谢作为丝氨酸/甘氨酸合成成瘾癌症的新治疗策略。