title: Combining histone deacetylase inhibitor vorinostat with aurora kinase inhibitors enhances lymphoma cell killing with repression of c-Myc, hTERT, and microRNA levels.
abstract: MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G(2)-M cell-cycle arrest. Growth and survival of multiple lymphoma cell lines were studied with either drug alone or in combination with vorinostat, a histone deacetylase inhibitor (HDACi), using MTS and Annexin V assays, followed by molecular studies. Either of the AKi alone at 100 to 500 nmol/L resulted in approximately 50% reduced cell growth and 10% to 40% apoptosis. Addition of vorinostat reactivated proapoptotic genes and enhanced lymphoma cell death. Quantitative PCR and immunoblotting revealed that epigenetic and protein acetylation mechanisms were responsible for this activity. The prosurvival genes Bcl-X(L) and hTERT were downregulated 5-fold by combination drug treatment, whereas the proapoptotic BAD and BID genes were upregulated 3-fold. The p53 tumor suppressor was stabilized by an increased acetylation in response to vorinostat and a reduced Ser315 phosphorylation in response to aurora kinase A. Vorinostat or trichostatin A decreased MYC mRNA and protein as well as c-Myc-regulated microRNAs. MYC is a critical gene in these responses, as MYC knockdown combined with the expression of the c-Myc antagonist MXD1 raised cell sensitivity to the effects of either AKi. Thus, the HDACi vorinostat leads to both transcriptional and posttranscriptional changes to create a proapoptotic milieu, sensitizing cells to mitosis-specific agents such as AKis.
authors.affiliation: Department of Translational Research, Clinical and Molecular Pharmacology, City of Hope and Beckman Research Institute, Duarte, California, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Kretzner
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Dino
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Kowolik
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Patrick
authors.initials: P
authors.lastname: Ventura
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kirschbaum
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D015151:Immunoblotting; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D000077337:Vorinostat; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064096:Aurora Kinase A; D064127:Aurora Kinases; D003509:Cyclohexanecarboxylic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D035683:MicroRNAs; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D019098:Telomerase; D013844:Thiazoles; D000077337:Vorinostat; C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; C489427:MYC protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C012589:trichostatin A; C576917:AURKA protein, human; C509186:TERT protein, human