Verapamil enhances the antitumoral efficacy of oncolytic adenoviruses.
The therapeutic potential of oncolytic adenoviruses is limited by the rate of adenovirus release. Based on the observation that several viruses induce cell death and progeny release by disrupting intracellular calcium homeostasis, we hypothesized that the alteration in intracellular calcium concentration induced by verapamil could improve the rate of virus release and spread, eventually enhancing the antitumoral activity of oncolytic adenoviruses. Our results indicate that verapamil substantially enhanced the release of adenovirus from a variety of cell types resulting in an improved cell-to-cell spread and cytotoxicity. Furthermore, the combination of the systemic administration of an oncolytic adenovirus (ICOVIR-5) with verapamil in vivo greatly improved its antitumoral activity in two different tumor xenograft models without affecting the selectivity of this virus. Overall, our findings indicate that verapamil provides a new, safe, and versatile way to improve the antitumoral potency of oncolytic adenoviruses in the clinical setting.
Gros
Alena
A
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
Puig
Cristina
C
Guedan
Sonia
S
Rojas
Juan José
JJ
Alemany
Ramon
R
Cascallo
Manel
M
D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014700:Verapamil / Q000627:therapeutic use*; D057074:Virus Release / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D014700:Verapamil