MiR-375-mediated suppression of engineered coxsackievirus B3 in pancreatic cells.

Markian Pryshliak,Ahmet Hazini,Beatrice Tolksdorf,Sandra Pinkert,Henry Fechner,Babette Dieringer,Jens Kurreck,Michele Solimena,Klaus Knoch

doi:10.1002/1873-3468.13647

Abstract

Coxsackievirus B3 (CVB3) has potential as a new oncolytic agent for the treatment of cancer but can induce severe pancreatitis. Here, we inserted target sequences of the microRNA miR-375 (miR-375TS) into the 5' terminus of the polyprotein encoding sequence or into the 3'UTR of the CVB3 strain rCVB3.1 to prevent viral replication in the pancreas. In pancreatic EndoC-βH1 cells expressing miR-375 endogenously, replication of the 5'-miR-375TS virus and that of the 3'-miR-375TS virus was reduced by 4×103 -fold and 3.9×104 -fold, respectively, compared to the parental rCVB3.1. In colorectal carcinoma cells, replication and cytotoxicity of both viruses were slightly reduced compared to rCVB3.1, but less pronounced for the 3'-miR-375TS virus. Thus, CVB3 with miR-375TS in the 3'UTR of the viral genome may be suitable to avoid pancreatic toxicity.

Highlights

Markian Pryshliak1, Ahmet Hazini1, Klaus Knoch2, Babette Dieringer1, Beatrice Tolksdorf1, Michele Solimena2, Jens Kurreck1, Sandra Pinkert3 and Henry Fechner1
FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
Our research focus is on the development of oncolytic Coxsackievirus B3 (CVB3) for treatment of colorectal carcinomas [15]

Summary

Introduction

Coxsackievirus B3 (CVB3) is a nonenveloped virus of the picornaviridae family, with an icosahedral capsid and a positive-sense, single-stranded RNA genome with a length of about 7.4 kb [1]. It has a short replication cycle of only 6–8 h and produces huge amounts of progeny virus [2]. Intratumoral injection of the CVB3 Nancy strain suppressed growth of subcutaneous human non–small-cell lung carcinomas in mice. We reported growth inhibition of subcutaneous human colorectal carcinomas in mice following intratumoral injection of three different CVB3 strains [15]. The virus did not induce significant treatment-related toxicity and mortality in nude mice, despite the fact that the virus was detected at moderate levels in the heart, lung, and kidney [12]

Methods

Results

Conclusion