Combined therapy of colon carcinomas with an oncolytic adenovirus and valproic acid

// Christian Bressy 1 , Dragomira Majhen 1 , Najat Raddi 1 , Wael Jdey 1 , Gaétan Cornilleau 1 , Léna Zig 1 , Josée Guirouilh-Barbat 2 , Bernard S. Lopez 2 , Olivia Bawa 3 , Paule Opolon 3 , Elodie Grellier 1 and Karim Benihoud 1 1 Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203 CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, Villejuif 94805, France 2 Laboratoire Recombinaison-Réparation et Cancer, UMR 8200 CNRS Stabilité Génétique et Oncogenèse, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, Villejuif 94805, France 3 Unité de pathologie expérimentale de l’IRCIV, Gustave Roussy, Villejuif 94805, France Correspondence to: Karim Benihoud, email: karim.benihoud@gustaveroussy.fr Keywords: colon; polyploidy; oncolytic adenovirus; DNA damage; HDACi Received: November 25, 2016 Accepted: August 04, 2017 Published: October 26, 2017 ABSTRACT The anti-tumor potential of oncolytic adenoviruses (CRAds) has been demonstrated in preclinical and clinical studies. While these agents failed to eradicate tumors when used as a monotherapy, they may be more effective if combined with conventional treatments such as radiotherapy or chemotherapy. This study seeks to evaluate the combination of a CRAd bearing a Δ24 deletion in E1A with valproic acid (VPA), a histone deacetylase inhibitor, for the treatment of human colon carcinomas. This combination led to a strong inhibition of cell growth both in vitro and in vivo compared to treatment with CRAd or VPA alone. This effect did not stem from a better CRAd replication and production in the presence of VPA. Inhibition of cell proliferation and cell death were induced by the combined treatment. Moreover, whereas cells treated only with CRAd displayed a polyploidy (> 4N population), this phenotype was increased in cells treated with both CRAd and VPA. In addition, the increase in polyploidy triggered by combined treatment with CRAd and VPA was associated with the enhancement of H2AX phosphorylation (γH2AX), a hallmark of DNA damage, but also with a decrease of several DNA repair proteins. Finally, viral replication (or E1A expression) was shown to play a key role in the observed effects since no enhancement of polyploidy nor increase in γH2AX were found following cell treatment with a replication-deficient Ad and VPA. Taken together, our results suggest that CRAd and VPA could be used in combination for the treatment of colon carcinomas.