title: Redox Signaling and Bioenergetics Influence Lung Cancer Cell Line Sensitivity to the Isoflavone ME-344.
abstract: ME-344 [(3R,4S)-3,4-bis(4-hydroxyphenyl)-8-methyl-3,4-dihydro-2H-chromen-7-ol] is a second-generation derivative natural product isoflavone presently under clinical development. ME-344 effects were compared in lung cancer cell lines that are either intrinsically sensitive or resistant to the drug and in primary immortalized human lung embryonic fibroblasts (IHLEF). Cytotoxicity at low micromolar concentrations occurred only in sensitive cell lines, causing redox stress, decreased mitochondrial ATP production, and subsequent disruption of mitochondrial function. In a dose-dependent manner the drug caused instantaneous and pronounced inhibition of oxygen consumption rates (OCR) in drug-sensitive cells (quantitatively significantly less in drug-resistant cells). This was consistent with targeting of mitochondria by ME-344, with specific effects on the respiratory chain (resistance correlated with higher glycolytic indexes). OCR inhibition did not occur in primary IHLEF. ME-344 increased extracellular acidification rates in drug-resistant cells (significantly less in drug-sensitive cells), implying that ME-344 targets mitochondrial proton pumps. Only in drug-sensitive cells did ME-344 dose-dependently increase the intracellular generation of reactive oxygen species and cause oxidation of total (mainly glutathione) and protein thiols and the concomitant immediate increases in NADPH levels. We conclude that ME-344 causes complex, redox-specific, and mitochondria-targeted effects in lung cancer cells, which differ in extent from normal cells, correlate with drug sensitivity, and provide indications of a beneficial in vitro therapeutic index.
authors.affiliation: Departments of Cell and Molecular Pharmacology and Experimental Therapeutics (Y.M., L.R., K.T.), Medicine (C.B.), and Drug Discovery and Biomedical Sciences (D.T.) of the Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Yefim
authors.initials: Y
authors.lastname: Manevich
authors.affiliation: Departments of Cell and Molecular Pharmacology and Experimental Therapeutics (Y.M., L.R., K.T.), Medicine (C.B.), and Drug Discovery and Biomedical Sciences (D.T.) of the Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Leticia
authors.initials: L
authors.lastname: Reyes
authors.affiliation: Departments of Cell and Molecular Pharmacology and Experimental Therapeutics (Y.M., L.R., K.T.), Medicine (C.B.), and Drug Discovery and Biomedical Sciences (D.T.) of the Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Britten
authors.affiliation: Departments of Cell and Molecular Pharmacology and Experimental Therapeutics (Y.M., L.R., K.T.), Medicine (C.B.), and Drug Discovery and Biomedical Sciences (D.T.) of the Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.affiliation: Departments of Cell and Molecular Pharmacology and Experimental Therapeutics (Y.M., L.R., K.T.), Medicine (C.B.), and Drug Discovery and Biomedical Sciences (D.T.) of the Medical University of South Carolina, Charleston, South Carolina tewk@musc.edu.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Tew
mesh_terms: D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007529:Isoflavones; C000597890:ME-344