title: Modulation of anthracycline-induced cytotoxicity by targeting the prenylated proteome in myeloid leukemia cells.
abstract: Deregulation of Ras/ERK signaling in myeloid leukemias makes this pathway an interesting target for drug development. Myeloid leukemia cell lines were screened for idarubicin-induced apoptosis, cell-cycle progression, cell-cycle-dependent MAP kinase kinase (MEK-1/2) activation, and Top2 expression. Cell-cycle-dependent activation of MEK/ERK signaling was blocked using farnesyltransferase inhibitor (FTI) BMS-214,662 and dual prenyltransferase inhibitor (DPI) L-778,123 to disrupt Ras signaling. Idarubicin caused a G2/M cell-cycle arrest characterized by elevated diphosphorylated MEK-1/2 and Top2α expression levels. The FTI/DPIs elicited distinct effects on Ras signaling, protein prenylation, cell cycling and apoptosis. Combining these FTI/DPIs with idarubicin synergistically inhibited proliferation of leukemia cell lines, but the L-778,123+idarubicin combination exhibited synergistic growth inhibition over a greater range of drug concentrations. Interestingly, combined FTI/DPI treatment synergistically inhibited cell proliferation, induced apoptosis and nearly completely blocked protein prenylation. Inhibition of K-Ras expression by RNA interference or blockade of its post-translational prenylation led to increased BMS-214,662-induced apoptosis. Our results suggest that nearly complete inhibition of protein prenylation using an FTI + DPI combination is the most effective method to induce apoptosis and to block anthracycline-induced activation of ERK signaling.
authors.affiliation: Department of Hematology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Fredrick O
authors.initials: FO
authors.lastname: Onono
authors.forename: H Peter
authors.initials: HP
authors.lastname: Spielmann
authors.forename: Thangaiah
authors.initials: T
authors.lastname: Subramanian
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Letizia
authors.initials: L
authors.lastname: Venturini
authors.forename: Iris
authors.initials: I
authors.lastname: Dallmann
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Christoph W M
authors.initials: CW
authors.lastname: Reuter
mesh_terms: D018943:Anthracyclines; D000951:Antigens, Neoplasm / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000075223:Poly-ADP-Ribose Binding Proteins; D017368:Protein Prenylation / Q000187:drug effects*
chemical_list: D018943:Anthracyclines; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007093:Imidazoles; D000075223:Poly-ADP-Ribose Binding Proteins; D001569:Benzodiazepines; C425231:L 778,123; D004122:Dimethylallyltranstransferase; D051231:Farnesyltranstransferase; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine; D015255:Idarubicin