title: Pharmacologic manipulations of mitochondrial membrane potential (DeltaPsim) selectively in glioma cells.
abstract: Metabolic control theory applies principles of bioenergetics for the control or management of complex diseases. Since metabolism is a general process underlying all biologic phenotypes, changes in metabolism can potentially modify phenotype. Therefore, it is reasonable to assume that experimental modulation of the availability of cellular energy can potentially alter cell phenotypes and cell functions critical to tumor progression including cell division. The purpose of this study was to determine if OMX-2, a methylquinone system designed to shuttle electrons from mitochondrial complexes, was able to target mitochondria in cancer cells and trigger cell death. Using flow cytometry, cell viability assays, and ATP measurements, we found that OMX-2 differentially decreased DeltaPsim without triggering cell death. In contrast, known blockers of the Electron Transport Chain (ETC) decreased DeltaPsim and triggered cell death. When normal cells were treated with OMX-2, neither DeltaPsim or cell death was triggered. Furthermore, OMX-2 modulated intracellular ATP and decreased cell numbers of glioma cells. Cell cycle analysis indicated that OMX-2 induced a reversible cell cycle arrest in G1/S. Finally, impairment of glycolysis by 2-Deoxyglucose (2-DOG) acted synergistically with OMX-2 to trigger cell death. Overall, these results indicate that it is possible to selectively target cancer cells by decreasing DeltaPsim and induced cell cycle arrest without triggering cell death. Moreover, pharmacological approaches designed to act on both glycolysis and oxidative phosphorylation can be considered as a new approach to selectively kill cancer cells.
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, 1918 University Blvd., THT 1046, Birmingham, AL 35294-0006, USA. cgriguer@uab.edu
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Griguer
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Oliva
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.forename: Eric
authors.initials: E
authors.lastname: Gobin
authors.forename: Pascale
authors.initials: P
authors.lastname: Marcorelles
authors.forename: G
authors.initials: G
authors.lastname: Yancey Gillespie
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology*; D045222:Electron Transport Chain Complex Proteins / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D045222:Electron Transport Chain Complex Proteins; C518177:OMX-2 compound; D011809:Quinones; D005947:Glucose