2-Deoxy-D-glucose increases the sensitivity of glioblastoma cells to BCNU through the regulation of glycolysis, ROS and ERS pathways: In vitro and in vivo validation

Xiaodong Sun; Tengjiao Fan; Guohui Sun; Yue Zhou; Yaxin Huang; Na Zhang; Lijiao Zhao; Rugang Zhong; Yongzhen Peng

doi:10.1016/j.bcp.2022.115029

2-Deoxy-D-glucose increases the sensitivity of glioblastoma cells to BCNU through the regulation of glycolysis, ROS and ERS pathways: In vitro and in vivo validation

Biochem Pharmacol. 2022 May:199:115029. doi: 10.1016/j.bcp.2022.115029. Epub 2022 Apr 4.

Authors

Xiaodong Sun¹, Tengjiao Fan², Guohui Sun³, Yue Zhou⁴, Yaxin Huang⁵, Na Zhang⁶, Lijiao Zhao⁷, Rugang Zhong⁸, Yongzhen Peng⁹

Affiliations

¹ Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: sunxd@emails.bjut.edu.cn.
² Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China; Department of Medical Technology, Beijing Pharmaceutical University of Staff and Workers, Beijing 100079, China. Electronic address: fannie818@126.com.
³ Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: sunguohui@bjut.edu.cn.
⁴ Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Xian Nong Tan Street, Beijing 100050, China. Electronic address: zhouyue@imm.ac.cn.
⁵ Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: huangyaxin@emails.bjut.edu.cn.
⁶ Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: nanatonglei@bjut.edu.cn.
⁷ Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: zhaolijiao@bjut.edu.cn.
⁸ Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: lifesci@bjut.edu.cn.
⁹ National Engineering Laboratory for Advanced Municipal Wastewater Treatment and Reuse Technology, College of Environmental and Chemical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: pyz@bjut.edu.cn.

PMID: 35381210
DOI: 10.1016/j.bcp.2022.115029

Abstract

Chloroethylnitrosoureas (CENUs) exert antitumor activity via producing dG-dC interstrand crosslinks (ICLs). However, tumor resistance make it necessary to find novel strategies to improve the therapeutic effect of CENUs. 2-Deoxy-D-glucose (2-DG) is a well-known glycolytic inhibitor, which can reprogram tumor energy metabolism closely related to tumor resistance. Here, we investigated the chemosensitization effect of 2-DG on l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against glioblastoma cells and the underlying mechanisms. We found that 2-DG significantly increased the inhibitory effects of BCNU on tumor cells compared with BCNU alone, while 2-DG showed no obvious enhancing effect on the BCNU-induced cytotoxicity for normal HaCaT and HA1800 cells. Proliferation, migration and invasion determinations presented the same trend as survival on tumor cells. 2-DG plus BCNU increased the energy deficiency through a more effective inhibition of glycolytic pathway. Notably, the combination of 2-DG and BCNU aggravated oxidative stress in glioblastoma cells, along with a significant decrease in glutathione (GSH) levels, and an increase in intracellular reactive oxygen species (ROS). Subsequently, we demonstrated that the combination treatment led to increased apoptosis via activating mitochondria and endoplasmic reticulum stress (ERS) related apoptosis pathways. Finally, we found that the dG-dC level was significantly increased after 2-DG pretreatment compared to BCNU alone by HPLC-ESI-MS/MS analysis. Finally, in vivo, 2-DG plus BCNU significantly suppressed tumor growth with lower side effects compared with BCNU alone in tumor-bearing mice. In summary, we proposed that 2-DG may have potential to increase the sensitivity of glioblastoma cells to BCNU by regulating glycolysis, ROS and ERS pathways in clinical setting.

Keywords: 2-Deoxy-D-glucose; Antitumor mechanism; BCNU; Chemosensitization; Combination therapy; Glioblastoma cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carmustine* / pharmacology
Deoxyglucose / pharmacology
Endoplasmic Reticulum Stress
Glioblastoma* / drug therapy
Glucose
Glutathione / metabolism
Glycolysis
Mice
Reactive Oxygen Species
Tandem Mass Spectrometry

Substances

Reactive Oxygen Species
Deoxyglucose
Glutathione
Glucose
Carmustine