title: Deciphering the molecular events necessary for synergistic tumor cell apoptosis mediated by the histone deacetylase inhibitor vorinostat and the BH3 mimetic ABT-737.
abstract: The concept of personalized anticancer therapy is based on the use of targeted therapeutics through in-depth knowledge of the molecular mechanisms of action of these agents when used alone and in combination. We have identified the apoptotic proteins and pathways necessary for synergistic tumor cell apoptosis and in vivo antitumor responses seen when the HDAC inhibitor vorinostat is combined with the BH3-mimetic ABT-737 in lymphomas overexpressing Bcl-2. Vorinostat "primes" tumors overexpressing Bcl-2 for rapid ABT-737-mediated apoptosis by inducing expression of the BH3-only gene bmf. Moreover, these synergistic effects of vorinostat/ABT-737 were blunted in cells with an inactive p53 pathway or in cells lacking expression of the p53 target gene, noxa. These studies show the important and complex functional interaction between specific proapoptotic BH3-only proteins and the BH3-mimetic compound ABT-737 and provide the most comprehensive functional link between tumor genotype and the apoptotic and therapeutic effects of HDACi combined with ABT-737.
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, The Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Wiegmans
authors.forename: Amber E
authors.initials: AE
authors.lastname: Alsop
authors.forename: Michael
authors.initials: M
authors.lastname: Bots
authors.forename: Leonie A
authors.initials: LA
authors.lastname: Cluse
authors.forename: Steven P
authors.initials: SP
authors.lastname: Williams
authors.forename: Kellie-Marie
authors.initials: KM
authors.lastname: Banks
authors.forename: Rachael
authors.initials: R
authors.lastname: Ralli
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
authors.forename: Anna
authors.initials: A
authors.lastname: Frenzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D016158:Genes, p53; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000077337:Vorinostat
chemical_list: C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat