title: HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells.
abstract: Enzastaurin is an investigational PKCβ inhibitor that has growth inhibitory and pro-apoptotic effects in both B and T-cell lymphomas. We investigated the cytotoxicity and mechanisms of cell death of the combination of enzastaurin and low concentrations of histone deacetylase (HDAC) inhibitors in B-cell and T-cell lymphoma cell lines and primary lymphoma/leukemia cells. Combined enzastaurin/suberoylanilide hydroxamic acid treatment synergistically induced apoptosis in diffuse large B-cell lymphoma and T-cell lymphoma cell lines, and primary lymphoma/leukemia samples. Similarly, combined treatment of B-cell-like lymphoma cells with enzastaurin and two different HDAC inhibitors, valproic acid and (2E,4E)-6-(4-chlorophenylsulfanyl)-2,4-hexadienoic acid hydroxyamide synergistically induced apoptosis, suggesting the synergy is generalizable to other HDAC inhibitors. Our data indicate that enzastaurin/HDAC inhibitors therapy can synergistically inhibit growth and induce apoptosis in lymphoid malignancies and may be an effective therapeutic strategy. Potential mechanisms including enzastaurin mediated inhibition of HDAC inhibitor-induced compensatory survival pathways are discussed.
authors.affiliation: Department of Clinical Pathology, Institute of Pathology and Laboratory Medicine, Cleveland Clinic, OH 44195, USA.
authors.forename: Juraj
authors.initials: J
authors.lastname: Bodo
authors.forename: Jan
authors.initials: J
authors.lastname: Sedlak
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: Alex
authors.initials: A
authors.lastname: Almasan
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008223:Lymphoma / Q000188:drug therapy*; D013440:Sulfides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D000077337:Vorinostat
chemical_list: C568358:6-(4-chlorophenylsulfanyl)-2,4-hexadienoic acid hydroxyamide; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D013440:Sulfides; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; D014635:Valproic Acid; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; C504878:enzastaurin