title: Histone deacetylase inhibitor NVP-LAQ824 sensitizes human nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation.
abstract: Stage III nonsmall cell lung cancer is primarily treated with combined chemotherapy and radiation therapy. Relapses for progression of disease within irradiated sites remains a primary pattern of failure. To evaluate the interaction between histone deacetylase inhibitors and irradiation in nonsmall cell lung cancer, we studied NVP-LAQ824 in mouse models of human lung cancer. Colony formation assays were performed to determine whether LAQ824 sensitized nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation. LAQ824 reduced clonogenic survival of the H23 and H460 cell lines five-fold compared with controls and four-fold compared with either agent alone (P<0.001). Western blot analysis of caspase cleavage, microscopic analysis of nuclei and Annexin-fluorescein isothiocyanate/propidium iodide flow cytometry assays showed that LAQ824 enhanced radiation-induced apoptosis and attenuated mitosis (P<0.001). Immunostaining for gamma-H2AX nuclear foci was performed to determine the effect of LAQ824 on radiation-induced DNA double-strand breaks. Combined modality treatment delayed the resolution of gamma-H2AX foci with over 30% of cells staining positive 6 h after treatment versus approximately 5 and 3% in cells treated with LAQ824 or radiation alone (P<0.001). Additionally, an in-vivo xenograft model was utilized to study the effects of fractioned irradiation and LAQ824 on tumor growth. Fractioned irradiation and LAQ824 delayed tumor growth by 19 days versus 7 and 4 days for treatment with LAQ824 and radiation alone. This study shows the effectiveness of histone deacetylase inhibitors to enhance the cytotoxic effects of radiation by attenuating DNA repair and inducing apoptosis in human nonsmall cell lung cancer.
authors.affiliation: Vanderbilt University School of Medicine, E1219 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA. kyle.cuneo@vanderbilt.edu
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Cuneo
authors.forename: Allie
authors.initials: A
authors.lastname: Fu
authors.forename: Katherine
authors.initials: K
authors.lastname: Osusky
authors.forename: Jessica
authors.initials: J
authors.lastname: Huamani
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.forename: Ling
authors.initials: L
authors.lastname: Geng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000032:analysis; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C477361:LAQ824; D011838:Radiation-Sensitizing Agents