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

Nat Commun. 2015 Mar 30;6:6410. doi: 10.1038/ncomms7410.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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