title: Combination therapy with the histone deacetylase inhibitor LBH589 and radiation is an effective regimen for prostate cancer cells.
abstract: Radiation therapy (RT) continues to be one of the most popular treatment options for localized prostate cancer (CaP). The purpose of the study was to investigate the in vitro effect of LBH589 alone and in combination with RT on the growth and survival of CaP cell lines and the possible mechanisms of radiosensitization of this combination therapy. The effect of LBH589 alone or in combination with RT on two CaP cell lines (PC-3 and LNCaP) and a normal prostatic epithelial cell line (RWPE-1) was studied by MTT and clonogenic assays, cell cycle analysis, western blotting of apoptosis-related and cell check point proteins, and DNA double strand break (DSB) repair markers. The immunofluorescence staining was used to further confirm DSB expression in treated CaP cells. Our results indicate that LBH589 inhibited proliferation in both CaP and normal prostatic epithelial cells in a time-and-dose-dependent manner; low-dose of LBH589 (IC20) combined with RT greatly improved efficiency of cell killing in CaP cells; compared to RT alone, the combination treatment with LBH589 and RT induced more apoptosis and led to a steady increase of sub-G1 population and abolishment of RT-induced G2/M arrest, increased and persistent DSB, less activation of non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathways and a panel of cell cycle related proteins. These results suggest that LBH589 is a potential agent to increase radiosensitivity of human CaP cells. LBH589 used either alone, or in combination with RT is an attractive strategy for treating human CaP.
authors.affiliation: Cancer Care Centre and Prostate Cancer Institute, St George Hospital, Kogarah, New South Wales, Australia.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xiao
authors.forename: Peter H
authors.initials: PH
authors.lastname: Graham
authors.forename: Jingli
authors.initials: J
authors.lastname: Hao
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.forename: Jie
authors.initials: J
authors.lastname: Ni
authors.forename: Carl A
authors.initials: CA
authors.lastname: Power
authors.forename: Qihan
authors.initials: Q
authors.lastname: Dong
authors.forename: John H
authors.initials: JH
authors.lastname: Kearsley
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004249:DNA Damage; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D000077767:Panobinostat; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D011995:Recombination, Genetic
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat