title: Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition.
abstract: Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors.
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ju
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China. Electronic address: caiyingye@126.com.
authors.forename: Caiying
authors.initials: C
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical Collage, 5 Dong Dan San Tiao, Beijing 100005, China. Electronic address: zhangdechang45@vip.sina.com.
authors.forename: Dechang
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014230:Triazoles; C062058:carboxyamido-triazole; D003847:Deoxyglucose; D005947:Glucose
keywords: 2-deoxyglucose; Carboxyamidotriazole; G2/M arrest; Glycolysis; Oxidative phosphorylation