title: Ionizing radiation enhances dl922-947-mediated cell death of anaplastic thyroid carcinoma cells.
abstract: dl922-947 is an oncolytic adenovirus potentially suitable for the treatment of aggressive localized tumors, such as anaplastic thyroid carcinoma (ATC). In this study, we have analyzed the effects of dl922-947 in combination with ionizing radiations, testing different schedules of administration and observing synergistic effects only when ATC cells were irradiated 24 h prior to viral infection. Cells undergoing combined treatment exhibited a marked increase in cell death and viral replication, suggesting that irradiation blocks cells in a more permissive state for viral life cycle. We also show that dl922-947 triggers a DNA damage response, characterized by mobilization of the MRN complex (composed by Mre11-Rad50-Nbs1), accumulation of γH2AX, and activation of the checkpoint kinases ataxia telangiectasia mutated (ATM) and Chk1. Based on these observations, we speculate that the DNA damage response acts as a cellular protective mechanism to hinder viral infection and replication. To confirm this hypothesis, we demonstrate that the ATM inhibitor KU55933 increased the oncolytic activity of dl922-947 and its replication. Finally, we validate the potential therapeutic use of this approach by showing in vivo that the combined treatment slows tumor xenograft growth more potently than either irradiation or infection alone.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Passaro
authors.forename: Antonella
authors.initials: A
authors.lastname: Abagnale
authors.forename: Silvana
authors.initials: S
authors.lastname: Libertini
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Volpe
authors.forename: Ginevra
authors.initials: G
authors.lastname: Botta
authors.forename: Laura
authors.initials: L
authors.lastname: Cella
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacelli
authors.forename: Gunnel
authors.initials: G
authors.lastname: Halldèn
authors.forename: David
authors.initials: D
authors.lastname: Gillespie
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Portella
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004249:DNA Damage; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D011839:Radiation, Ionizing; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000473:pathology / Q000628:therapy*; D047368:Tumor Burden; D014779:Virus Replication
keywords: DNA damage; anaplastic thyroid carcinoma; irradiation; oncolytic virus