title: Inhibition of autophagy enhances the effects of E1A-defective oncolytic adenovirus dl922-947 against glioma cells in vitro and in vivo.
abstract: Oncolytic viruses represent a novel therapeutic approach for aggressive tumors, such as glioblastoma multiforme, which are resistant to available treatments. Autophagy has been observed in cells infected with oncolytic viruses; however, its role in cell death/survival is unclear. To elucidate the potential therapeutic use of autophagy modulators in association with viral therapy, we analyzed autophagy induction in human glioma cell lines U373MG and U87MG infected with the oncolytic adenovirus dl922-947. dl922-947 infection triggered an autophagic cellular response, as shown by the development of acidic vesicular organelles, LC3-I→LC3-II conversion, and reduction of p62 levels. However, on infection, the Akt/mTOR/p70s6k pathway, which negatively regulates autophagy, was activated, whereas the ERK1/2 pathway, a positive regulator of autophagy, was inhibited. Accordingly, MEK inhibition by PD98059 sensitized glioma cells to dl922-947 effects, whereas autophagy induction by rapamycin protected cells from dl922-947-induced death. Treatment with two inhibitors of autophagy, chloroquine and 3-methyladenine, increased the cytotoxic effects of dl922-947 in vitro. In vivo, the growth of U87MG-induced xenografts was further reduced by adding chloroquine to the dl922-947 treatment. In conclusion, autophagy acts as a survival response in glioma cells infected with dl922-947, thus suggesting autophagy inhibitors as adjuvant/neoadjuvant drugs in oncolytic virus-based treatments.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, 80131, Naples, Italy.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Botta
authors.forename: Carmela
authors.initials: C
authors.lastname: Passaro
authors.forename: Silvana
authors.initials: S
authors.lastname: Libertini
authors.forename: Antonella
authors.initials: A
authors.lastname: Abagnale
authors.forename: Sara
authors.initials: S
authors.lastname: Barbato
authors.forename: Angela Serena
authors.initials: AS
authors.lastname: Maione
authors.forename: Gunnel
authors.initials: G
authors.lastname: Hallden
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Portella
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D005910:Glioma / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D017500:Adenovirus E1A Proteins; D000276:Adjuvants, Immunologic; C025946:3-methyladenine; D002738:Chloroquine; D000225:Adenine