期刊
CANCER LETTERS
卷 519, 期 -, 页码 30-45出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.06.015
关键词
Mitochondria; Reactive oxygen species; Autophagy; Senescence; Tricarboxylic acid cycle
类别
资金
- National Natural Science Foundation of China [81703004, U1904151, 81772832, 32000271, 22073023]
- Young Backbone Teacher in Colleges and Universities of Henan Province [2020GGJS033]
- Postdoctoral Research Foundation of China [2019M652527, 2020M672214]
- Start-up Fund of Postdoctoral Research Program of Henan Province [1901009]
- Postgraduate Education Reform Project of Henan Province [2019SJGLX081Y]
- Innovative Research Team (in Science and Technology) in University of Henan Province [19IRTSTHN004]
- Guangdong Provincial Key Laboratory of Drug Non-clinical Evaluation and Research [2018B030323024]
In this study, the novel naphthalimide derivative 6c was found to suppress CRC tumor growth and metastasis by inhibiting oxidative phosphorylation and the tricarboxylic acid cycle, leading to oxidative stress and inducing cell death and senescence. The combination of 6c and mitoxantrone showed stronger inhibitory effects on CRC by inducing reactive oxygen species production and autophagic cell death. These findings suggest that 6c may be a promising candidate for CRC treatment.
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Oxidative phosphorylation (OXPHOS) has attracted a considerable attention in CRC. It is of great interest to explore novel therapies that inhibit OXPHOS for CRC treatment. Compound 6c is a novel naphthalimide derivative. However, the effects of 6c on CRC and the underlying mechanism are unclear. In this study, 6c suppressed CRC tumor growth and metastasis. RNA-seq data showed that 6c triggered the inhibition of OXPHOS and tricarboxylic acid cycle. 6c specifically inhibited mitochondrial complex III activity and the expression of isocitrate dehydrogenase 2 (IDH2), resulting in oxidative stress. Antioxidants reversed 6c-induced cell death, senescence, and autophagosomes formation. 6c inhibited autophagy flux; however, pretreatment with autophagy inhibitors resulted in the reduction of 6cinduced cytoplasmic vacuolization and proliferation inhibition. Moreover, combinatory treatment of 6c and mitoxantrone (MIT) showed stronger inhibitory effects on CRC compared with the single agent. Downregulation of IDH2 induced reactive oxygen species production, leading to MIT accumulation and autophagic cell death after co-treatment with 6c and MIT. In summary, our findings indicated 6c as a promising candidate for CRC treatment.
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