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代谢连接性分析揭示肿瘤中氧化还原稳态破坏与联合用药疗效的关系

Disruption of redox homeostasis for combinatorial drug efficacy in tumors as revealed by metabolic connectivity profiling.

作者信息

Gaglio Daniela, Bonanomi Marcella, Valtorta Silvia, Bharat Rohit, Ripamonti Marilena, Conte Federica, Fiscon Giulia, Righi Nicole, Napodano Elisabetta, Papa Federico, Raccagni Isabella, Parker Seth J, Cifola Ingrid, Camboni Tania, Paci Paola, Colangelo Anna Maria, Vanoni Marco, Metallo Christian M, Moresco Rosa Maria, Alberghina Lilia

机构信息

Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, MI Italy.

ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126 Milan, Italy.

出版信息

Cancer Metab. 2020 Sep 29;8:22. doi: 10.1186/s40170-020-00227-4. eCollection 2020.

DOI:10.1186/s40170-020-00227-4
PMID:33005401
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7523077/
Abstract

BACKGROUND

Rewiring of metabolism induced by oncogenic in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways.

METHODS

We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity.

RESULTS

We show that -mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism.

CONCLUSIONS

Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.

摘要

背景

致癌作用诱导的癌细胞代谢重编程涉及葡萄糖和谷氨酰胺的利用，维持增强的、不受限制的生长。识别和合理组合靶向代谢途径可能有助于开发针对代谢的有效抗癌治疗方法。

方法

我们进行了质谱代谢组学分析以及体外和体内实验，以评估药物疗效并识别代谢连通性。

结果

我们表明，-突变型肺癌和结肠癌细胞表现出独特的代谢重编程，后者对呼吸作用的依赖性更强。谷氨酰胺酶抑制剂CB-839和PI3K/醛缩酶抑制剂NVP-BKM120联合治疗更持续地降低肿瘤异种移植瘤的细胞生长。最大生长抑制与氧化还原稳态的破坏相关，包括还原型谷胱甘肽再生的丧失、氧化还原辅助因子以及主要参与核酸代谢的代谢物之间连通性的降低。

结论

我们的研究结果为将代谢连通性分析发展成为一种工具开辟了道路，该工具可用于精准肿瘤学中联合药物重新定位的选择性策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/3390c09a400f/40170_2020_227_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/1e7ccc1623e6/40170_2020_227_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/10421f07ae7f/40170_2020_227_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/38472acecd13/40170_2020_227_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/efa6e2ed5a55/40170_2020_227_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/4b69058bfcb6/40170_2020_227_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/3390c09a400f/40170_2020_227_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/1e7ccc1623e6/40170_2020_227_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/10421f07ae7f/40170_2020_227_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/38472acecd13/40170_2020_227_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/efa6e2ed5a55/40170_2020_227_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/4b69058bfcb6/40170_2020_227_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d07/7523077/3390c09a400f/40170_2020_227_Fig6_HTML.jpg

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1
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2
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Curr Opin Biotechnol. 2020 Jun;63:177-189. doi: 10.1016/j.copbio.2020.02.005. Epub 2020 Mar 18.
3
Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis.使用MetaboAnalyst 4.0进行全面综合的代谢组学数据分析。
沃伯格效应解析：增强的糖酵解与异质性线粒体的整合促进癌细胞增殖。
Int J Mol Sci. 2023 Oct 31;24(21):15787. doi: 10.3390/ijms242115787.
4
Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.转录组学与代谢组学整合揭示乳腺癌细胞中氧化还原依赖性代谢重编程
Cancers (Basel). 2021 Oct 9;13(20):5058. doi: 10.3390/cancers13205058.
5
Metabolism-related long non-coding RNAs (lncRNAs) as potential biomarkers for predicting risk of recurrence in breast cancer patients.代谢相关长链非编码RNA（lncRNA）作为预测乳腺癌患者复发风险的潜在生物标志物。
Bioengineered. 2021 Dec;12(1):3726-3736. doi: 10.1080/21655979.2021.1953216.
6
GEO data mining and TCGA analysis reveal altered branched chain amino acid metabolism in pancreatic cancer patients.GEO 数据挖掘和 TCGA 分析显示胰腺癌患者支链氨基酸代谢改变。
Aging (Albany NY). 2021 Apr 21;13(8):11907-11918. doi: 10.18632/aging.202892.
7
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Cancers (Basel). 2021 Jan 22;13(3):399. doi: 10.3390/cancers13030399.
8
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