title: Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids.
abstract: There is a strong rationale for targeting the metabolic alterations of cancer cells. The most studied of these are the higher rates of glycolysis, glutaminolysis and de novo synthesis of fatty acids (FAs). Despite the availability of pharmacological inhibitors of these pathways, no preclinical studies targeting them simultaneously have been performed. In the present study it was determined whether three key enzymes for glycolysis, glutaminolysis and de novo synthesis of FAs, hexokinase-2, glutaminase and fatty acid synthase, respectively, were overexpressed as compared to primary fibroblasts. In addition, we showed that at clinically relevant concentrations lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat, known inhibitors of the mentioned enzymes, exerted a cell viability inhibitory effect. Genetic downregulation of the three enzymes also reduced cell viability. The three drugs were highly synergistic when administered as a triple combination. Of note, the cytotoxicity of the triple combination was low in primary fibroblasts and was well tolerated when administered into healthy BALB/c mice. The results suggest the feasibility and potential clinical utility of the triple metabolic targeting which merits to be further studied by using either repositioned old drugs or newer, more selective inhibitors.
authors.affiliation: Division of Basic Research, Instituto Nacional de Cancerología, Mexico City, Tlalpan 14080, Mexico.
authors.forename: Diana
authors.initials: D
authors.lastname: Cervantes-Madrid
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM)/Instituto Nacional de Cancerología, Mexico City, Tlalpan 14080, Mexico.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Dueñas-González
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003980:Diazooxonorleucine / Q000008:administration & dosage; D004357:Drug Synergism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D007783:Lactones / Q000008:administration & dosage; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000077403:Orlistat
chemical_list: D005227:Fatty Acids; D007191:Indazoles; D007783:Lactones; D003980:Diazooxonorleucine; D000077403:Orlistat; D064429:Fatty Acid Synthases; D006593:Hexokinase; D005972:Glutaminase; C016371:lonidamine