Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O 6-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation

被引:3
作者
Huang, Yaxing [1 ]
Wang, Peng [2 ]
Fan, Tengjiao [1 ,3 ]
Zhang, Na [1 ]
Zhao, Lijiao [1 ]
Zhong, Rugang [1 ]
Sun, Guohui [1 ]
机构
[1] Beijing Univ Technol, Coll Chem & Life Sci, Beijing Key Lab Environm & Viral Oncol, Beijing 100124, Peoples R China
[2] First Med Ctr Chinese PLA Gen Hosp, Dept Neurosurg, Beijing 100853, Peoples R China
[3] Beijing Pharmaceut Univ Staff & Workers, Dept Med Technol, Beijing 100079, Peoples R China
基金
中国国家自然科学基金; 北京市自然科学基金;
关键词
lonidamine; ACNU; glioblastoma; MGMT; resistance; chemo-sensitization; INTERSTRAND CROSS-LINKING; MELANOMA XENOGRAFTS; CANCER; CHLOROETHYLNITROSOUREAS; CYTOTOXICITY; NITROSOUREAS; METABOLISM; MECHANISM; THERAPY; REPAIR;
D O I
10.1021/acsptsci.4c00085
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Tumor resistance seriously hinders the clinical application of chloroethylnitrosoureas (CENUs), such as O-6-methylguanine-DNA methylguanine (MGMT), which can repair O-6-alkyl lesions, thereby inhibiting the formation of cytotoxic DNA interstrand cross-links (ICLs). Metabolic differences between tumor and normal cells provide a biochemical basis for novel therapeutic strategies aimed at selectively inhibiting tumor energy metabolism. In this study, the energy blocker lonidamine (LND) was selected as a chemo-sensitizer of nimustine (ACNU) to explore its potential effects and underlying mechanisms in human glioblastoma in vitro and in vivo. A series of cell-level studies showed that LND significantly increased the cytotoxic effects of ACNU on glioblastoma cells. Furthermore, LND plus ACNU enhanced the energy deficiency by inhibiting glycolysis and mitochondrial function. Notably, LND almost completely downregulated MGMT expression by inducing intracellular acidification. The number of lethal DNA ICLs produced by ACNU increased after the LND pretreatment. The combination of LND and ACNU aggravated cellular oxidative stress. In resistant SF763 mouse tumor xenografts, LND plus ACNU significantly inhibited tumor growth with fewer side effects than ACNU alone. Finally, we proposed a new "HMAGOMR" chemo-sensitizing mechanism through which LND may act as a potential chemo-sensitizer to reverse ACNU resistance in glioblastoma: moderate inhibition of hexokinase (HK) activity (H); mitochondrial dysfunction (M); suppressing adenosine triphosphate (ATP)-dependent drug efflux (A); changing redox homeostasis to inhibit GSH-mediated drug inactivation (G) and increasing intracellular oxidative stress (O); downregulating MGMT expression through intracellular acidification (M); and partial inhibition of energy-dependent DNA repair (R).
引用
收藏
页码:1518 / 1532
页数:15
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