Skip to Content
Merck
  • Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing.

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

Nature communications (2015-03-31)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Propidium iodide, ≥94.0% (HPLC)
Sigma-Aldrich
Methanol, anhydrous, 99.8%
Supelco
Cycloheximide, PESTANAL®, analytical standard
Sigma-Aldrich
Sodium chloride, BioUltra, for molecular biology, ≥99.5% (AT)
Sigma-Aldrich
Sodium chloride, random crystals, optical grade, 99.9% trace metals basis
Sigma-Aldrich
Sodium chloride-35Cl, 99 atom % 35Cl
Sigma-Aldrich
Propidium iodide, ≥94% (HPLC)
Sigma-Aldrich
Nocodazole, ≥99% (TLC), powder
Sigma-Aldrich
Cycloheximide, Biotechnology Performance Certified
Sigma-Aldrich
Methanol, NMR reference standard
Sigma-Aldrich
Cycloheximide, from microbial, ≥94% (TLC)
SAFC
Sodium chloride solution, 5 M
SAFC
HEPES
Albendazole, European Pharmacopoeia (EP) Reference Standard
SAFC
HEPES
Paclitaxel semi-synthetic for peak identification, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
Sigma-Aldrich
Methanol, suitable for HPLC, gradient grade, ≥99.9%
Sigma-Aldrich
Methanol, suitable for HPLC, gradient grade, suitable as ACS-grade LC reagent, ≥99.9%
Supelco
HEPES, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Methanol, puriss., meets analytical specification of Ph Eur, ≥99.7% (GC)
Sigma-Aldrich
Methanol, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8% (GC)
Sigma-Aldrich
Ammonium chloride, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, 99.5-100.5% (calc. to the dried substance)
Sigma-Aldrich
Methanol, Laboratory Reagent, ≥99.6%
Sigma-Aldrich
Methanol, suitable for HPLC, ≥99.9%
Sigma-Aldrich
Methanol, HPLC Plus, ≥99.9%
Sigma-Aldrich
HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
Sigma-Aldrich
HEPES, ≥99.5% (titration)
Sigma-Aldrich
Cycloheximide, ≥90% (HPLC)
Sigma-Aldrich
Ammonium chloride, ReagentPlus®, ≥99.5%