清晨好,您是今天最早来到科研通的研友!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您科研之路漫漫前行!

Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis–Addicted Breast Tumor Growth

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 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
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:20 (1): 50-63 被引量:76
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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
10秒前
南城完成签到 ,获得积分10
15秒前
20秒前
20秒前
39秒前
明亮的小兔子完成签到 ,获得积分10
42秒前
solution完成签到 ,获得积分10
44秒前
46秒前
MchemG发布了新的文献求助10
47秒前
Tong完成签到,获得积分0
48秒前
1分钟前
1分钟前
luluw完成签到 ,获得积分10
1分钟前
甄雨琦发布了新的文献求助10
1分钟前
1分钟前
fys131415完成签到 ,获得积分10
1分钟前
1分钟前
1分钟前
科研通AI6.2应助senli2018采纳,获得10
1分钟前
v0id应助科研通管家采纳,获得10
1分钟前
1分钟前
Marwa21发布了新的文献求助10
1分钟前
2分钟前
2分钟前
senli2018发布了新的文献求助10
2分钟前
2分钟前
共享精神应助初景采纳,获得10
2分钟前
怀谷发布了新的文献求助30
2分钟前
2分钟前
2分钟前
ranqiang完成签到,获得积分20
2分钟前
xiaofeixia完成签到 ,获得积分10
2分钟前
一天完成签到 ,获得积分10
2分钟前
Eden完成签到 ,获得积分10
2分钟前
欧阳完成签到 ,获得积分10
2分钟前
3分钟前
3分钟前
3分钟前
初景发布了新的文献求助10
3分钟前
久晓完成签到 ,获得积分10
3分钟前
高分求助中
(应助此贴封号)【重要!!请各用户(尤其是新用户)详细阅读】【科研通的精品贴汇总】 10000
Common Foundations of American and East Asian Modernisation: From Alexander Hamilton to Junichero Koizumi 1000
Weaponeering: An Introduction Fourth Edition, Volume 1 1000
Advanced Weaponeering Fourth Edition, Volume 2 1000
Evidence Summary. Injection (subcutaneous):op- timal administration 1000
悉尼大学博士学位论文,题目:Modelling and testing of one-sided stitched laminated composites. 作者:Kristopher P. Plain 700
Matrix Methods in Data Mining and Pattern Recognition Second Edition 610
热门求助领域 (近24小时)
化学 材料科学 医学 生物 纳米技术 工程类 有机化学 化学工程 生物化学 计算机科学 内科学 物理 复合材料 催化作用 细胞生物学 无机化学 光电子学 物理化学 电极 基因
热门帖子
关注 科研通微信公众号,转发送积分 7497182
求助须知:如何正确求助?哪些是违规求助? 9088167
关于积分的说明 19383179
捐赠科研通 7107761
什么是DOI,文献DOI怎么找? 3250149
关于科研通互助平台的介绍 2419646
邀请新用户注册赠送积分活动 2235951