title: Inhibition of protein synthesis and JNK activation are not required for cell death induced by anisomycin and anisomycin analogues.
abstract: Anisomycin was identified in a screen of clinical compounds as a drug that kills breast cancer cells (MDA16 cells, derived from the triple negative breast cancer cell line, MDA-MB-468) that express high levels of an efflux pump, ABCB1. We show the MDA16 cells died by a caspase-independent mechanism, while MDA-MB-468 cells died by apoptosis. There was no correlation between cell death and either protein synthesis or JNK activation, which had previously been implicated in anisomycin-induced cell death. In addition, anisomycin analogues that did not inhibit protein synthesis or activate JNK retained the ability to induce cell death. These data suggest that either a ribosome-ANS complex is a death signal in the absence of JNK activation or ANS kills cells by binding to an as yet unidentified target.
authors: Pharmacology and Therapeutics, National Centre for Biomedical Engineering Research, National University of Ireland Galway, Galway, Ireland.
authors: David
authors: D
authors: Monaghan
authors: Screening Laboratory, National Centre for Biomedical Engineering Research, National University of Ireland Galway, Galway, Ireland.
authors: Enda
authors: E
authors: O'Connell
authors: School of Chemistry, University of Edinburgh, UK.
authors: Faye L
authors: FL
authors: Cruickshank
authors: Pharmacology and Therapeutics, National Centre for Biomedical Engineering Research, National University of Ireland Galway, Galway, Ireland.
authors: Barry
authors: B
authors: O'Sullivan
authors: HRB Clinical Research Facility, Galway, Ireland.
authors: Francis J
authors: FJ
authors: Giles
authors: School of Chemistry, University of Edinburgh, UK.
authors: Alison N
authors: AN
authors: Hulme
authors: Pharmacology and Therapeutics, National Centre for Biomedical Engineering Research, National University of Ireland Galway, Galway, Ireland. Electronic address: howard.fearnhead@nuigalway.ie.
authors: Howard O
authors: HO
authors: Fearnhead
mesh_terms: D000841:Anisomycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*
chemical_list: D011500:Protein Synthesis Inhibitors; D000841:Anisomycin; D048670:MAP Kinase Kinase 4
keywords: (2R,3R)-3-acetoxy-1-benzyl-2-(4-methoxybenzyl)pyrrolidine; (2R,3R,4S)-3-acetoxy-1-benzyl-2-(4-methoxybenzyl)-4-methylpyrrolidine; (2R,3S,4S)-1-benzyl-4-benzyloxy-3-hydroxy-2-(4-methoxybenzyl)pyrrolidine; (2R,3S,4S)-3-acetoxy-1-benzyl-4-benzyloxy-2-(4-methoxybenzyl)pyrrolidine; ANS; Apoptosis; Breast cancer; CHX; Compound 17; Compound 25; Compound 26; Compound 27; DMEM; DMSO; DTT; Drug-resistance; Dulbecco’s modified Eagle’s medium; FBS; HBSS; Hanks’ balanced salt solution; JNK; Jun kinase; PBS; PVDF; Ribotoxic stress; TBS; TNBC; anisomycin; cycloheximide; dimethyl sulfoxide; dithiolthreitol; fetal bovine serum; phosphate buffered saline; polyvinylidene difluoride; triple negative breast cancer; tris buffered saline