title: Flavaglines target primitive leukemia cells and enhance anti-leukemia drug activity.
abstract: Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Callahan
authors.affiliation: Division of Hematology, University of Colorado, Denver, Aurora, CO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Minhajuddin
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Corbett
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Lagadinou
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Rossi
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Grose
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Balys
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jacob
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Frontier
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Grever
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Lucas
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Kinghorn
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Liesveld
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Division of Hematology, University of Colorado, Denver, Aurora, CO, USA.
authors.forename: C T
authors.initials: CT
authors.lastname: Jordan
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D001572:Benzofurans / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects; D014315:Triterpenes / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001572:Benzofurans; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; C489897:silvestrol; C401859:temsirolimus; C107772:rocaglamide; D020123:Sirolimus