title: PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in vitro and in vivo model of anaplastic thyroid carcinoma.
abstract: PARP inhibitors are mostly effective as anticancer drugs in association with DNA damaging agents. We have previously shown that the oncolytic adenovirus dl922-947 induces extensive DNA damage, therefore we hypothesized a synergistic antitumoral effect of the PARP inhibitor olaparib in association with dl922-947. Anaplastic thyroid carcinoma was chosen as model since it is a particularly aggressive tumor and, because of its localized growth, it is suitable for intratumoral treatment with oncolytic viruses. Here, we show that dl922-947 infection induces PARP activation, and we confirm in vitro and in vivo that PARP inhibition increases dl922-947 replication and oncolytic activity. In vitro, the combination with olaparib exacerbates the appearance of cell death markers, such as Annexin V positivity, caspase 3 cleavage, cytochrome C release and propidium iodide permeability. In vivo, we also observed a better viral distribution upon PARP inhibition. Changes in CD31 levels suggest a direct effect of olaparib on tumor vascularization and on the viral distribution within the tumor mass. The observation that PARP inhibition enhances the effects of dl922-947 is highly promising not only for the treatment of anaplastic thyroid carcinoma but, in general, for the treatment of other tumors that could benefit from the use of oncolytic viruses.
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Passaro
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Volpe
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Botta
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy.
authors.forename: Eloise
authors.initials: E
authors.lastname: Scamardella
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perruolo
authors.affiliation: The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gillespie
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy; The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK. Electronic address: silvanalibertini@yahoo.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Libertini
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy. Electronic address: portella@unina.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Portella
mesh_terms: D000256:Adenoviridae; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D065646:Thyroid Carcinoma, Anaplastic / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: Anaplastic thyroid carcinoma; Oncolytic virus; PARP inhibitors