title: Synergistic effect of inhibiting translation initiation in combination with cytotoxic agents in acute myelogenous leukemia cells.
abstract: We have previously shown that inhibition of translation initiation, using the small molecule inhibitor silvestrol, induces apoptosis in a pre-clinical murine lymphoma model when combined with daunorubicin. Silvestrol blocks ribosome recruitment by targeting the RNA helicase, eIF4A, which is required for this process. Here we investigate the sensitivity of acute myelogenous leukemia (AML) cell lines to protein synthesis inhibition in combination with the standard cytotoxic agents daunorubicin, etoposide, and cytarabine. Silvestrol shows synergy with standard-of-care agents in AML cell lines and synergizes with ABT-737, a small molecule inhibitor of Bcl-X(L) and Bcl-2. The in vitro synergy between silvestrol and the cytotoxic drugs used in AML therapy provides a basis for in vivo evaluation of these combinations.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: Marilyn
authors.initials: M
authors.lastname: Carrier
authors.forename: Amanda
authors.initials: A
authors.lastname: Trnkus
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology; D003603:Cytotoxins / Q000008:administration & dosage* / Q000494:pharmacology; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008954:Models, Biological; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D020298:U937 Cells; D001572:Benzofurans
chemical_list: D001713:Biphenyl Compounds; D003561:Cytarabine; D003603:Cytotoxins; D003630:Daunorubicin; D005047:Etoposide; D009596:Nitrophenols; D010448:Peptide Initiation Factors; D010879:Piperazines; D011500:Protein Synthesis Inhibitors; D013449:Sulfonamides; D014315:Triterpenes; C501332:ABT-737; C489897:silvestrol; D001572:Benzofurans