title: Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress.
abstract: Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types.
authors.affiliation: Department of Cell Biology, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Huaping
authors.initials: H
authors.lastname: Liu
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Metin
authors.initials: M
authors.lastname: Kurtoglu
authors.affiliation: Cell Death Regulation Group, Bellvitage Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Clara Lucia
authors.initials: CL
authors.lastname: León-Annicchiarico
authors.affiliation: Cell Death Regulation Group, Bellvitage Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Munoz-Pinedo
authors.affiliation: Department of Pediatrics, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Barredo
authors.affiliation: Department of Pediatrics, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Leclerc
authors.affiliation: Department of Medicine, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Merchan
authors.affiliation: Department of Cell Biology, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Xiongfei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Lampidis
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D000960:Hypolipidemic Agents; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D011345:Fenofibrate
keywords: 2-deoxy-D-glucose; eIF2α; energy stress; fenofibrate; mTOR