biostudies-literatureXu YChinese Academy of SciencesScience and Technology Commission of Shanghai MunicipalityNational Natural Science Foundation of ChinaYouth Innovation Promotion Association of the Chinese Academy of Sciences7763-7769https://www.ebi.ac.uk/biostudies/studies/S-EPMC8188586biostudies-literatureUnknown12(22)The extraordinarily rapid growth of malignant tumors depends heavily on the glucose metabolism by the pathways of glycolysis and mitochondrial oxidative phosphorylation to generate adenosine 5'-triphosphate (ATP) for maintaining cell proliferation and tumor growth. This study reports a tumor chemical suffocation therapeutic strategy by concurrently suppressing both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) <i>via</i> the co-deliveries of EDTA and rotenone into a glutathione (GSH)-overexpressed tumor microenvironment. EDTA is to block the glycolytic pathway through inhibiting the activity of glycolytic enzymes <i>via</i> the chelation of magnesium ion, a co-worker of glycolytic enzymes, despite the presence of Ca²⁺. Meanwhile rotenone is to inhibit the mitocChemical scienceTumor chemical suffocation therapy by dual respiratory inhibitions.PMC8188586ZDBS-LY-SLH0292019No. 21835007No. 5207239419QA1410100Guo YChen LNi DShi JXu YHu PfalseTumor chemical suffocation therapy by dual respiratory inhibitions.The extraordinarily rapid growth of malignant tumors depends heavily on the glucose metabolism by the pathways of glycolysis and mitochondrial oxidative phosphorylation to generate adenosine 5'-triphosphate (ATP) for maintaining cell proliferation and tumor growth. This study reports a tumor chemical suffocation therapeutic strategy by concurrently suppressing both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) <i>via</i> the co-deliveries of EDTA and rotenone into a glutathione (GSH)-overexpressed tumor microenvironment. EDTA is to block the glycolytic pathway through inhibiting the activity of glycolytic enzymes <i>via</i> the chelation of magnesium ion, a co-worker of glycolytic enzymes, despite the presence of Ca²⁺. Meanwhile rotenone is to inhibit the mitoc2021-01-01T00:00:00Z2021 Apr2025-06-01T02:31:08.697Z2025-06-01T02:31:08.697ZS-EPMC81885863416882910.1039/d1sc00929j