title: Low dose histone deacetylase inhibitor, LBH589, potentiates anticancer effect of docetaxel in epithelial ovarian cancer via PI3K/Akt pathway in vitro.
abstract: The purpose of this study was to investigate the effect of combination of LBH589 with docetaxel (DTX) on the growth and survival of epithelial ovarian cancer (EOC) cells in vitro and the possible mechanisms of chemo-sensitization of LBH589 in the combination treatment. The effect of LBH589 alone or in combination with DTX on four EOC cell lines (OVCAR-3, IGROV-1, A2780 and SKOV-3) was studied by MTT and clonogenic assays, acridine orange (AO)/ethidium bromide (EB) staining for apoptosis, Western blotting for apoptosis-related proteins, histone H3 and H4 proteins, DNA double strand break (DSB) repair marker and phosphorylation of Akt. LBH589 alone inhibited EOC cell proliferation in a time and dose-dependent manner. Low-dose of LBH589 (IC(20)) combined with DTX had an additive effect and greatly improved efficacy of DTX cell killing in EOC cells. Compared to DTX alone, the combination treatment with LBH589 and DTX induced more apoptosis and led to an increased and persistent DSB. Cell death following single or combined treatment was associated with the release of cytochrome c activity, increased caspase-3 (active) and PARP-1(cleaved), histone acetylation-related proteins and PI3k/Akt signaling pathway. Our results suggest that LBH589 enhances DTX-induced apoptosis in human EOC cells, and can be used in combination with DTX as an attractive strategy for treating human EOC.
authors.affiliation: Department of Gynecologic Oncology, Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Hongtu
authors.initials: H
authors.lastname: Chao
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Jingli
authors.initials: J
authors.lastname: Hao
authors.forename: Jie
authors.initials: J
authors.lastname: Ni
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.forename: Peter H
authors.initials: PH
authors.lastname: Graham
authors.forename: John H
authors.initials: JH
authors.lastname: Kearsley
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D043823:Taxoids; D000077143:Docetaxel; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3