Suppression of oxidative phosphorylation and IDH2 sensitizes colorectal cancer to a naphthalimide derivative and mitoxantrone

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 6c-induced 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.