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A novel strategy for glioblastoma treatment by induction of noptosis, an NQO1-dependent necrosis
Zhong, Bingling1; Yu, Jie1; Hou, Ying1; Ai, Nana2; Ge, Wei2; Lu, Jin Jian1; Chen, Xiuping1
2021-04-01
Source PublicationFree Radical Biology and Medicine
ISSN0891-5849
Volume166Pages:104-115
Abstract

Glioblastoma (GBM) is one of the most prevalent malignant primary tumors in the human brain. Temozolomide (TMZ), the chemotherapeutic drug for GBM treatment, induces apoptosis. Unfortunately, apoptosis-resistance to TMZ results in treatment failure. GBM shows enhanced expression of NAD(P)H: quinone oxidoreductase 1 (NQO1). Recently, noptosis, a type of NQO1-dependent necrosis, was proposed. Here, we identified that tanshindiol B (TSB) inhibits GBM growth by induction of noptosis. TSB triggered significant cell death, which did not fit the criteria of apoptosis but oxidative stress-induced necrosis. Molecular docking, cellular thermal shift assay, and NQO1 activity assay revealed that TSB bind to and promptly activated NQO1 enzyme activity. As the substrate of NQO1, TSB induced oxidative stress, which resulted in dramatic DNA damage, poly (ADP-ribose) polymerase 1 (PARP1) hyperactivation, and NAD depletion, leading to necrotic cell death. These effects of TSB were completely abolished by specific NQO1 inhibitor dicoumarol (DIC). Furthermore, the c-Jun N-terminal kinase 1/2 (JNK1/2) plays an essential role in mediating TSB-induced cell death. Besides, TSB significantly suppressed tumor growth in a zebrafish xenograft model mediated by NQO1. In conclusion, these results showed that TSB was an NQO1 substrate and triggered noptosis of GBM. TSB exhibited anti-tumor potentials in GBM both in vitro and in vivo. This study provides a novel strategy for fighting GBM through the induction of noptosis.

KeywordGlioblastoma Jnk1/2 Noptosis Nqo1 Tanshindiol b
DOI10.1016/j.freeradbiomed.2021.02.014
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS SubjectBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS IDWOS:000632701800003
Scopus ID2-s2.0-85101502523
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Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorChen, Xiuping
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
2.Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macau, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zhong, Bingling,Yu, Jie,Hou, Ying,et al. A novel strategy for glioblastoma treatment by induction of noptosis, an NQO1-dependent necrosis[J]. Free Radical Biology and Medicine,2021,166:104-115.
APA Zhong, Bingling,Yu, Jie,Hou, Ying,Ai, Nana,Ge, Wei,Lu, Jin Jian,&Chen, Xiuping.(2021).A novel strategy for glioblastoma treatment by induction of noptosis, an NQO1-dependent necrosis.Free Radical Biology and Medicine,166,104-115.
MLA Zhong, Bingling,et al."A novel strategy for glioblastoma treatment by induction of noptosis, an NQO1-dependent necrosis".Free Radical Biology and Medicine 166(2021):104-115.
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