title: Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells.
abstract: Therapeutic advances have markedly prolonged overall survival in multiple myeloma (MM) but the disease currently remains incurable. In a panel of MM cell lines (MM.1S, OPM-2, H929, and U266), using CD138 immunophenotyping, side population staining, and stem cell-related gene expression, we demonstrate the presence of stem-like tumor cells. Hypoxic culture conditions further increased CD138low stem-like cells with upregulated expression of OCT4 and NANOG. Compared to MM cells, these stem-like cells maintained lower steady-state pro-oxidant levels with increased uptake of the fluorescent deoxyglucose analog. In primary human MM samples, increased glycolytic gene expression correlated with poorer overall and event-free survival outcomes. Notably, stem-like cells showed increased mitochondrial mass, rhodamine 123 accumulation, and orthodox mitochondrial configuration while more condensed mitochondria were noted in the CD138high cells. Glycolytic inhibitor 2-deoxyglucose (2-DG) induced ER stress as detected by qPCR (BiP, ATF4) and immunoblotting (BiP, CHOP) and increased dihydroethidium probe oxidation both CD138low and CD138high cells. Treatment with a mitochondrial-targeting agent decyl-triphenylphosphonium (10-TPP) increased intracellular steady-state pro-oxidant levels in stem-like and mature MM cells. Furthermore, 10-TPP mediated increases in mitochondrial oxidant production were suppressed by ectopic expression of manganese superoxide dismutase. Relative to 2-DG or 10-TPP alone, 2-DG plus 10-TPP combination showed increased caspase 3 activation in MM cells with minimal toxicity to the normal hematopoietic progenitor cells. Notably, treatment with polyethylene glycol conjugated catalase significantly reduced 2-DG and/or 10-TPP-induced apoptosis of MM cells. Also, the combination of 2-DG with 10-TPP decreased clonogenic survival of MM cells. Taken together, this study provides a novel strategy of metabolic oxidative stress-induced cytotoxicity of MM cells via 2-DG and 10-TPP combination therapy.
authors.affiliation: Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Schibler
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Tomanek-Chalkley
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Reedy
authors.affiliation: Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA, United States of America.|Department of Internal Medicine, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, United States of America.|Department of Radiology, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schultz
authors.affiliation: Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA, United States of America.|Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Apollina
authors.initials: A
authors.lastname: Goel
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D004347:Drug Interactions; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D009861:Onium Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D009861:Onium Compounds; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; C000621063:decyltriphenylphosphonium; D003847:Deoxyglucose; D005947:Glucose