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: Rozanne Arulanandam, Cory Batenchuk, Oliver Varette, Chadi Zakaria, Vanessa Garcia, Nicole E Forbes, Colin Davis, Ramya Krishnan, Raunak Karmacharya, Julie Cox, Anisha Sinha, Andrew Babawy, Katherine Waite, Erica Weinstein, Theresa Falls, Andrew Chen, Jeff Hamill, Naomi De Silva, David P Conrad, Harold Atkins, Kenneth Garson, Carolina Ilkow, Mads Kærn, Barbara Vanderhyden, Nahum Sonenberg, Tommy Alain, Fabrice Le Boeuf, John C Bell, Jean-Simon Diallo
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6410 (Mar 30 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25817275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• Cytokines
• Interferon Type I
• RNA, Messenger
• Tubulin Modulators
• Vinblastine
• Albendazole
• parbendazole
• Vinorelbine
• Nocodazole
• Colchicine

Topics

• Albendazole (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Bystander Effect (drug effects, immunology)
• Cell Line
• Cell Line, Tumor
• Chlorocebus aethiops
• Colchicine (pharmacology)
• Cytokines (drug effects, immunology)
• HT29 Cells
• Humans
• Interferon Type I (drug effects, genetics, metabolism)
• Mice
• Microtubules (drug effects)
• Nocodazole (pharmacology)
• Oncolytic Virotherapy
• Oncolytic Viruses
• Protein Biosynthesis (drug effects)
• RNA, Messenger (drug effects, metabolism)
• Rhabdoviridae
• Rhabdoviridae Infections (immunology)
• Tubulin Modulators (pharmacology)
• Vero Cells
• Vinblastine (analogs & derivatives, pharmacology)
• Vinorelbine