Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

• Published in: Nature communications Vol. 6; no. 1; p. 6410
• Main Authors: Arulanandam, Rozanne, Batenchuk, Cory, Varette, Oliver, Zakaria, Chadi, Garcia, Vanessa, Forbes, Nicole E., Davis, Colin, Krishnan, Ramya, Karmacharya, Raunak, Cox, Julie, Sinha, Anisha, Babawy, Andrew, Waite, Katherine, Weinstein, Erica, Falls, Theresa, Chen, Andrew, Hamill, Jeff, De Silva, Naomi, Conrad, David P., Atkins, Harold, Garson, Kenneth, Ilkow, Carolina, Kærn, Mads, Vanderhyden, Barbara, Sonenberg, Nahum, Alain, Tommy, Le Boeuf, Fabrice, Bell, John C., Diallo, Jean-Simon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.03.2015; Nature Publishing Group
• Subjects: 13/21; 631/250/127/1212; 631/67/1059/99; 631/80/128/1653; 64/60; 96/1; 96/31; 96/63; 96/95; Albendazole - pharmacology; Animals; Apoptosis; Benzimidazoles - pharmacology; Biological weapons; Bystander Effect - drug effects; Bystander Effect - immunology; Cancer; Cell death; Cell Line; Cell Line, Tumor; Cellular structure; Cercopithecus aethiops; Colchicine - pharmacology; Cytokines; Cytokines - drug effects; Cytokines - immunology; Destabilization; Disruption; Drug dosages; Fibroblasts; Gene expression; Genetic engineering; HT29 Cells; Humanities and Social Sciences; Humans; Immunotherapy; Infections; Interferon; Interferon Type I - drug effects; Interferon Type I - genetics; Interferon Type I - metabolism; Medical research; Mice; Microtubules - drug effects; multidisciplinary; Nocodazole - pharmacology; Oncolytic Virotherapy; Oncolytic Viruses; Protein Biosynthesis - drug effects; Protein expression; Proteins; Rhabdoviridae; Rhabdoviridae Infections - immunology; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Tubulin Modulators - pharmacology; Tumors; Vero Cells; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; Vinorelbine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7410

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. Microtubule-destabilizing drugs and oncolytic viruses are two unrelated approaches to battle cancer. Here the authors show that microtubule-destabilizing drugs potentiate the efficiency of oncolytic rhabdoviruses by altering the cytokine production and response of the tumour cells.