title: Cationic liposome-mediated delivery of reovirus enhances the tumor cell-killing efficiencies of reovirus in reovirus-resistant tumor cells.
abstract: Reovirus induces tumor cell death efficiently and specifically, and thus is currently undergoing clinical testing as an anticancer agent. In the intracellular trafficking of reovirus, proteolytic disassembly of reovirus capsid-proteins and subsequent penetration of viral particles into the cytosol are crucial steps. Cathepsins B and L are largely responsible for the proteolytic disassembly of reovirus. Reovirus efficiently lyses tumor cells exhibiting relatively high activities of cathepsins B and L, while tumor cells with low activities of cathepsins B and L are often refractory to reovirus, probably due to inefficient endo/lysosomal escape. In this study, in order to enhance the tumor cell-killing efficiencies of reovirus by promoting endo/lysosomal escape, especially in reovirus-resistant tumor cells, reovirus was complexed with a cationic liposome transfection reagent. Reovirus alone and reovirus-cationic liposome complex (reoplex) exhibited similar levels of tumor cell-killing efficiencies in reovirus-susceptible tumor cells, while reoplex mediated more than 30% higher levels of tumor cell-killing activities in reovirus-resistant tumor cells than reovirus alone. Reoplex-mediated tumor cell death was efficiently induced in the tumor cells pretreated with cathepsin inhibitors. The mRNA levels of interferon (IFN)-β and apoptotic genes were significantly elevated following reoplex treatment. These results suggest that cationic liposomes efficiently promoted delivery of reovirus to the cytosol, leading to induction of apoptosis.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan; Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Unit, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. Electronic address: sakurai@phs.osaka-u.ac.jp.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sakurai
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Tadataka
authors.initials: T
authors.lastname: Kaminade
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Hotani
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katayama
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Hosoyamada
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Terasawa
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tachibana
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan; Laboratory of Hepatic Differentiation Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D002401:Cathepsin B; D056668:Cathepsin L; D002412:Cations; D002460:Cell Line; D006801:Humans; D008055:Lipids; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D050130:Oncolytic Virotherapy; D012087:Reoviridae; D014162:Transfection
chemical_list: D002412:Cations; D008055:Lipids; C086724:Lipofectamine; D008081:Liposomes; D002401:Cathepsin B; D056668:Cathepsin L
keywords: Cathepsin; Cationic lipid; Oncolytic virus; Reovirus; Transfection