title: AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization.
abstract: Cancer cells have a unique metabolic profile and mitochondria have been shown to play an important role in chemoresistance, tumor progression and metastases. This unique profile can be exploited by mitochondrial-targeted anticancer therapies. A small anticancer molecule, AG311, was previously shown to possess anticancer and antimetastatic activity in two cancer mouse models and to induce mitochondrial depolarization. This study defines the molecular effects of AG311 on the mitochondria to elucidate its observed efficacy. AG311 was found to competitively inhibit complex I activity at the ubiquinone-binding site. Complex I as a target for AG311 was further established by measuring oxygen consumption rate in tumor tissue isolated from AG311-treated mice. Cotreatment of cells and animals with AG311 and dichloroacetate, a pyruvate dehydrogenase kinase inhibitor that increases oxidative metabolism, resulted in synergistic cell kill and reduced tumor growth. The inhibition of mitochondrial oxygen consumption by AG311 was found to reduce HIF-1α stabilization by increasing oxygen tension in hypoxic conditions. Taken together, these results suggest that AG311 at least partially mediates its antitumor effect through inhibition of complex I, which could be exploited in its use as an anticancer agent.
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
authors.forename: Anja
authors.initials: A
authors.lastname: Bastian
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuzaki
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Humphries
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States.
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Pharaoh
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
authors.forename: Arpit
authors.initials: A
authors.lastname: Doshi
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Zaware
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK 73117, United States. Electronic address: michael-ihnat@ouhsc.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ihnat
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: C000597961:5-((4-methylphenyl)thio)-9H-pyrimido(4,5-b)indole-2,4-diamine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011743:Pyrimidines; D042967:Electron Transport Complex I
keywords: Anticancer compound; Electron transport chain; Hypoxia; Mitochondrial metabolism; NADH-ubiquinone oxidoreductase