Blockade of Glutathione Metabolism in IDH1-Mutated Glioma

被引：71

作者：

Tang, Xiaoying ^{[1
]}

Fu, Xiao ^{[1
,2
]}

Liu, Yang ^{[2
]}

Yu, Di ^{[2
]}

Cai, Sabrina J. ^{[2
]}

Yang, Chunzhang ^{[2
]}

机构：

[1] Beijing Inst Technol, Sch Life Sci & Technol, Beijing, Peoples R China

[2] NCI, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2020年 / 19卷 / 01期

关键词：

ISOCITRATE DEHYDROGENASE; OXIDATIVE STRESS; GAUCHER-DISEASE; INHIBITION; MUTATIONS; IDH1; NRF2; ACTIVATION; GROWTH; CELLS;

D O I：

10.1158/1535-7163.MCT-19-0103

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated IDHs exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against IDH1-mutated solid tumor remains unavailable. In this study, we showed that acquisition of IDH1 mutation results in the disruption of NADP(+)/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting GSH synthesis and reactive oxygen species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on IDH1-mutated cancer in vitro and in vivo. Our findings highlight a possible therapeutic strategy that could be valuable for IDH1-mutated cancer treatment.

引用

页码：221 / 230

页数：10

共 45 条

[21] Double-barreled gun: Combination of PARP inhibitor with conventional chemotherapy [J].

Lu, Yanxin ;

Liu, Yang ;

Pang, Ying ;

Pacak, Karel ;

Yang, Chunzhang .

PHARMACOLOGY & THERAPEUTICS, 2018, 188 :168-175

[22] Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair [J].

Lu, Yanxin ;

Kwintkiewicz, Jakub ;

Liu, Yang ;

Tech, Katherine ;

Frady, Lauren N. ;

Su, Yu-Ting ;

Bautista, Wendy ;

Moon, Seog In ;

MacDonald, Jeffrey ;

Ewend, Matthew G. ;

Gilbert, Mark R. ;

Yang, Chunzhang ;

Wu, Jing .

CANCER RESEARCH, 2017, 77 (07) :1709-1718

[23]

MEISTER A, 1994, CANCER RES, V54, pS1969

[24] IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas [J].

Nobusawa, Sumihito ;

Watanabe, Takuya ;

Kleihues, Paul ;

Ohgaki, Hiroko .

CLINICAL CANCER RESEARCH, 2009, 15 (19) :6002-6007

[25] Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2 [J].

Olayanju, Adedamola ;

Copple, Ian M. ;

Bryan, Holly K. ;

Edge, George T. ;

Sison, Rowena L. ;

Wong, Min Wei ;

Lai, Zheng-Quan ;

Lin, Zhi-Xiu ;

Dunn, Karen ;

Sanderson, Christopher M. ;

Alghanem, Ahmad F. ;

Cross, Michael J. ;

Ellis, Ewa C. ;

Ingelman-Sundberg, Magnus ;

Malik, Hassan Z. ;

Kitteringham, Neil R. ;

Goldring, Christopher E. ;

Park, B. Kevin .

FREE RADICAL BIOLOGY AND MEDICINE, 2015, 78 :202-212

[26] Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma [J].

Pang, Ying ;

Lu, Yanxin ;

Caisova, Veronika ;

Liu, Yang ;

Bullova, Petra ;

Thanh-Truc Huynh ;

Zhou, Yiqiang ;

Yu, Di ;

Frysak, Zdenek ;

Hartmann, Igor ;

Taieb, David ;

Pacak, Karel ;

Yang, Chunzhang .

CLINICAL CANCER RESEARCH, 2018, 24 (14) :3423-3432

[27]

PENG XL, 2019, JNCI-J NATL CANCER I, DOI DOI 10.1007/S00432-019-03047-2

[28] The Two Faces of Reactive Oxygen Species in Cancer [J].

Reczek, Colleen R. ;

Chandel, Navdeep S. .

ANNUAL REVIEW OF CANCER BIOLOGY, VOL 1, 2017, 1 :79-98

[29] Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism [J].

Ren, Dongmei ;

Villeneuve, Nicole F. ;

Jiang, Tao ;

Wu, Tongde ;

Lau, Alexandria ;

Toppin, Henry A. ;

Zhang, Donna D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (04) :1433-1438

[30] An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells [J].

Rohle, Dan ;

Popovici-Muller, Janeta ;

Palaskas, Nicolaos ;

Turcan, Sevin ;

Grommes, Christian ;

Campos, Carl ;

Tsoi, Jennifer ;

Clark, Owen ;

Oldrini, Barbara ;

Komisopoulou, Evangelia ;

Kunii, Kaiko ;

Pedraza, Alicia ;

Schalm, Stefanie ;

Silverman, Lee ;

Miller, Alexandra ;

Wang, Fang ;

Yang, Hua ;

Chen, Yue ;

Kernytsky, Andrew ;

Rosenblum, Marc K. ;

Liu, Wei ;

Biller, Scott A. ;

Su, Shinsan M. ;

Brennan, Cameron W. ;

Chan, Timothy A. ;

Graeber, Thomas G. ;

Yen, Katharine E. ;

Mellinghoff, Ingo K. .

SCIENCE, 2013, 340 (6132) :626-630

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