title: Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing.
abstract: In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Rozanne
authors: R
authors: Arulanandam
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Cory
authors: C
authors: Batenchuk
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Oliver
authors: O
authors: Varette
authors: Department of Biochemistry, Goodman Cancer Center, McGill University, 1160 Pine Avenue West, Montréal, Quebec, Canada H3A 1A3.
authors: Chadi
authors: C
authors: Zakaria
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Vanessa
authors: V
authors: Garcia
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Nicole E
authors: NE
authors: Forbes
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Colin
authors: C
authors: Davis
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Ramya
authors: R
authors: Krishnan
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Raunak
authors: R
authors: Karmacharya
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Julie
authors: J
authors: Cox
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Anisha
authors: A
authors: Sinha
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Andrew
authors: A
authors: Babawy
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Katherine
authors: K
authors: Waite
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Erica
authors: E
authors: Weinstein
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Theresa
authors: T
authors: Falls
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Andrew
authors: A
authors: Chen
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Jeff
authors: J
authors: Hamill
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Naomi
authors: N
authors: De Silva
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: David P
authors: DP
authors: Conrad
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Harold
authors: H
authors: Atkins
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Kenneth
authors: K
authors: Garson
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Carolina
authors: C
authors: Ilkow
authors: Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors: Mads
authors: M
authors: Kærn
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Barbara
authors: B
authors: Vanderhyden
authors: Department of Biochemistry, Goodman Cancer Center, McGill University, 1160 Pine Avenue West, Montréal, Quebec, Canada H3A 1A3.
authors: Nahum
authors: N
authors: Sonenberg
authors: Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors: Tommy
authors: T
authors: Alain
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Fabrice
authors: F
authors: Le Boeuf
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: John C
authors: JC
authors: Bell
authors: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors: Jean-Simon
authors: JS
authors: Diallo
mesh_terms: D015766:Albendazole / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D024201:Bystander Effect / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003078:Colchicine / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects* / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D007370:Interferon Type I / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D015739:Nocodazole / Q000494:pharmacology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D012209:Rhabdoviridae; D018353:Rhabdoviridae Infections / Q000276:immunology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D014709:Vero Cells; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D001562:Benzimidazoles; D016207:Cytokines; D007370:Interferon Type I; D012333:RNA, Messenger; D050257:Tubulin Modulators; D014747:Vinblastine; D015766:Albendazole; C100292:parbendazole; D000077235:Vinorelbine; D015739:Nocodazole; D003078:Colchicine