Glycolytic inhibition by 3-bromopyruvate increases the cytotoxic effects of chloroethylnitrosoureas to human glioma cells and the DNA interstrand cross-links formation. (15th April 2020)

• Record Type: Journal Article
• Authors: Sun, Xiaodong; Sun, Guohui; Huang, Yaxin; Zhang, Shufen; Tang, Xiaoyu; Zhang, Na; Zhao, Lijiao; Zhong, Rugang; Peng, Yongzhen
• Is Part Of: Toxicology. Volume 435(2020)
• Publication Date: 2020-04-15
• Subjects: ICLs interstrand cross-links -- CENUs chloroethylnitrosoureas -- MGMT O6-methylguanine-DNA methyltransferase -- 3-BrPA 3-bromopyruvate -- BCNU l, 3-bis(2-chloroethyl)-l-nitrosourea -- GSH glutathione -- O6-ClEtG O6-chloroethylguanine -- N1, O6-EtG N1, O6-ethanoguanine -- O6-BG O6-benzylguanine -- O6-4-BTG O6-(4-bromothenyl)guanine -- ROS reactive oxygen species -- GST glutathione S-transferase -- TCA trichloroacetic acid -- FBS fetal bovine serum -- PBS phosphate buffered saline -- DNTB 5, 5′-dithiobis(2-nitrobenxoic acid) -- CEIC chloroethylisocyanate -- HPLC-ESI-MS/MS high-performance liquid chromatography electrospray ionization tandem mass spectrometry -- SRM selecting reaction monitoring -- CID collision induced dissociation; DNA interstrand cross-links (ICLs) -- Chloroethylnitrosoureas (CENUs) -- Cytotoxicity -- Human glioma cells -- 3-Bromopyruvate (3-BrPA) -- Glycolytic inhibitor; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2020.152413
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: Glycolytic inhibitor 3-BrPA increased the cytotoxicity of CENUs to glioma cells. 3-BrPA decreased the levels of extracellular lactate, cellular ATP and GSH. 3-BrPA in combination with BCNU produced more significant inhibition. 3-BrPA significantly increased the levels of dG-dC ICLs induced by BCNU. Glycolytic inhibition is promising to reverse the clinical CENUs chemoresistance. Abstract: DNA interstrand cross-links (ICLs) are essential for the antitumor activity of chloroethylnitrosoureas (CENUs). Commonly, CENUs resistance is mainly considered to be associated with O 6 -methylguanine-DNA methyltransferase (MGMT) within tumors. Bypassing the MGMT-mediated resistance, to our knowledge, herein, we first utilized a novel glycolytic inhibitor, 3-bromopyruvate (3-BrPA), to increase the cytotoxic effects of l, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to human glioma cells based on the hypothesis that blocking energy metabolism renders tumor cells more sensitive to chemotherapy. We found 3-BrPA significantly increased the cell killing by BCNU in human glioma SF763 and SF126 cell lines. Significantly decreased levels of extracellular lactate, cellular ATP and glutathione (GSH) were observed after 3-BrPA treatment, and the effects were more remarkable with 3-BrPA in combination with BCNU. Considering that the role of ATP and GSH in drug efflux, DNA damage repair and drug inactivation, we determined the effect of 3-BrPA on the formation of dG-dC ICLs induced by BCNU using stable isotope dilution high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). As expected, the levels of lethal dG-dC ICLs induced by BCNU were obviously enhanced after 3-BrPA pretreatment. Based on these results, 3-BrPA and related glycolytic inhibitors may be promising to enhance the cell killing effect and reverse the clinical chemoresistance of CENUs and related antitumor agents.