title: Inhibition of fatty acid metabolism reduces human myeloma cells proliferation.
abstract: Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.
authors.affiliation: Unidad de Investigación, Hospital Universitario Puerta del Mar, Cádiz, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Tirado-Vélez
authors.forename: Insaf
authors.initials: I
authors.lastname: Joumady
authors.forename: Ana
authors.initials: A
authors.lastname: Sáez-Benito
authors.forename: Irene
authors.initials: I
authors.lastname: Cózar-Castellano
authors.forename: Germán
authors.initials: G
authors.lastname: Perdomo
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D050260:Carbohydrate Metabolism / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002569:Cerulenin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D004852:Epoxy Compounds / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D009101:Multiple Myeloma; D000077403:Orlistat; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D001897:Boronic Acids; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004852:Epoxy Compounds; D005227:Fatty Acids; D007783:Lactones; D011719:Pyrazines; D016160:Retinoblastoma Protein; D002569:Cerulenin; D000069286:Bortezomib; D000077403:Orlistat; D005947:Glucose; C054207:etomoxir