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Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma

Dimethyl fumarate (DMF) is an approved drug used in the treatment of multiple sclerosis (MS) and psoriasis therapy. Multiple studies have demonstrated other pharmacological activities of DMF such as an anti-cancer agent. In particular, studies have shown that DMF can modulate the NRF2/HO1/NQO1 antio...

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Autores principales: Chen, Kaiyuan, Wu, Shanshan, Ye, Sisi, Huang, Huimin, Zhou, Yi, Zhou, Hongfei, Wu, Shijia, Mao, Yefan, Shangguan, Fugen, Lan, Linhua, Chen, Bicheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937954/
https://www.ncbi.nlm.nih.gov/pubmed/33692690
http://dx.doi.org/10.3389/fphar.2021.617714
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author Chen, Kaiyuan
Wu, Shanshan
Ye, Sisi
Huang, Huimin
Zhou, Yi
Zhou, Hongfei
Wu, Shijia
Mao, Yefan
Shangguan, Fugen
Lan, Linhua
Chen, Bicheng
author_facet Chen, Kaiyuan
Wu, Shanshan
Ye, Sisi
Huang, Huimin
Zhou, Yi
Zhou, Hongfei
Wu, Shijia
Mao, Yefan
Shangguan, Fugen
Lan, Linhua
Chen, Bicheng
author_sort Chen, Kaiyuan
collection PubMed
description Dimethyl fumarate (DMF) is an approved drug used in the treatment of multiple sclerosis (MS) and psoriasis therapy. Multiple studies have demonstrated other pharmacological activities of DMF such as an anti-cancer agent. In particular, studies have shown that DMF can modulate the NRF2/HO1/NQO1 antioxidant signal pathway and inactivate NF-κB to suppress the growth of colon and breast cancer cells, and induce cell death. In this study, we aimed to evaluate the anti-tumor activities of DMF in pancreatic cancer (PC) focusing on cell death as the predominant mechanism of response. We showed that both mitochondrial respiration and aerobic glycolysis were severely depressed following treatment with DMF and the effects could be abrogated by treatment with L-cysteine and N-acetyl-L-cysteine (NAC). Importantly, we verified that DMF induced metabolic crisis and that cell death was not related to alterations in ROS. Our data implied that MTHFD1 could be a potential downstream target of DMF identified by molecular docking analysis. Finally, we confirmed that MTHFD1 is up-regulated in PC and overexpression of MTHFD1 was negatively related to outcomes of PC patients. Our data indicate that DMF induces metabolic crisie to suppress cell growth and could be a potential novel therapy in the treatment of PC.
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spelling pubmed-79379542021-03-09 Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma Chen, Kaiyuan Wu, Shanshan Ye, Sisi Huang, Huimin Zhou, Yi Zhou, Hongfei Wu, Shijia Mao, Yefan Shangguan, Fugen Lan, Linhua Chen, Bicheng Front Pharmacol Pharmacology Dimethyl fumarate (DMF) is an approved drug used in the treatment of multiple sclerosis (MS) and psoriasis therapy. Multiple studies have demonstrated other pharmacological activities of DMF such as an anti-cancer agent. In particular, studies have shown that DMF can modulate the NRF2/HO1/NQO1 antioxidant signal pathway and inactivate NF-κB to suppress the growth of colon and breast cancer cells, and induce cell death. In this study, we aimed to evaluate the anti-tumor activities of DMF in pancreatic cancer (PC) focusing on cell death as the predominant mechanism of response. We showed that both mitochondrial respiration and aerobic glycolysis were severely depressed following treatment with DMF and the effects could be abrogated by treatment with L-cysteine and N-acetyl-L-cysteine (NAC). Importantly, we verified that DMF induced metabolic crisis and that cell death was not related to alterations in ROS. Our data implied that MTHFD1 could be a potential downstream target of DMF identified by molecular docking analysis. Finally, we confirmed that MTHFD1 is up-regulated in PC and overexpression of MTHFD1 was negatively related to outcomes of PC patients. Our data indicate that DMF induces metabolic crisie to suppress cell growth and could be a potential novel therapy in the treatment of PC. Frontiers Media S.A. 2021-02-22 /pmc/articles/PMC7937954/ /pubmed/33692690 http://dx.doi.org/10.3389/fphar.2021.617714 Text en Copyright © 2021 Chen, Wu, Ye, Huang, Zhou, Zhou, Wu, Mao, Shangguan, Lan and Chen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Chen, Kaiyuan
Wu, Shanshan
Ye, Sisi
Huang, Huimin
Zhou, Yi
Zhou, Hongfei
Wu, Shijia
Mao, Yefan
Shangguan, Fugen
Lan, Linhua
Chen, Bicheng
Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma
title Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma
title_full Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma
title_fullStr Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma
title_full_unstemmed Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma
title_short Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma
title_sort dimethyl fumarate induces metabolic crisie to suppress pancreatic carcinoma
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937954/
https://www.ncbi.nlm.nih.gov/pubmed/33692690
http://dx.doi.org/10.3389/fphar.2021.617714
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