Zhong Bingling, Yu Jie, Hou Ying, Ai Nana, Ge Wei, Lu Jin-Jian, Chen Xiuping
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China.
Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Free Radic Biol Med. 2021 Apr;166:104-115. doi: 10.1016/j.freeradbiomed.2021.02.014. Epub 2021 Feb 15.
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.
胶质母细胞瘤（GBM）是人类大脑中最常见的原发性恶性肿瘤之一。替莫唑胺（TMZ）是用于治疗GBM的化疗药物，可诱导细胞凋亡。不幸的是，对TMZ的凋亡抗性导致治疗失败。GBM中烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）：醌氧化还原酶1（NQO1）的表达增强。最近，有人提出了一种NQO1依赖性坏死——非凋亡性坏死（noptosis）。在此，我们发现丹参二醇B（TSB）通过诱导非凋亡性坏死来抑制GBM生长。TSB引发了显著的细胞死亡，这不符合凋亡的标准，但符合氧化应激诱导的坏死。分子对接、细胞热位移分析和NQO1活性分析表明，TSB与NQO1结合并迅速激活其酶活性。作为NQO1的底物，TSB诱导氧化应激，导致严重的DNA损伤、聚（ADP-核糖）聚合酶1（PARP1）过度激活和NAD耗竭，从而导致坏死性细胞死亡。特异性NQO1抑制剂双香豆素（DIC）完全消除了TSB的这些作用。此外，c-Jun氨基末端激酶1/2（JNK1/2）在介导TSB诱导的细胞死亡中起重要作用。此外，TSB在由NQO1介导的斑马鱼异种移植模型中显著抑制肿瘤生长。总之，这些结果表明TSB是一种NQO1底物，并引发GBM的非凋亡性坏死。TSB在体外和体内均表现出对GBM的抗肿瘤潜力。本研究为通过诱导非凋亡性坏死对抗GBM提供了一种新策略。
