Cargando…

Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan

Reovirus is a double stranded RNA virus, with an intrinsic preference for replication in KRAS mutant cells. As 45% of human colorectal cancers (CRC) harbor KRAS mutations, we sought to investigate its efficacy in KRAS mutant CRC cells, and examine its impact in combination with the topoisimerase-1 i...

Descripción completa

Detalles Bibliográficos
Autores principales: Maitra, Radhashree, Seetharam, Raviraja, Tesfa, Lydia, Augustine, Titto A., Klampfer, Lidija, Coffey, Matthew C., Mariadason, John M., Goel, Sanjay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058046/
https://www.ncbi.nlm.nih.gov/pubmed/24798549
_version_ 1782321061534105600
author Maitra, Radhashree
Seetharam, Raviraja
Tesfa, Lydia
Augustine, Titto A.
Klampfer, Lidija
Coffey, Matthew C.
Mariadason, John M.
Goel, Sanjay
author_facet Maitra, Radhashree
Seetharam, Raviraja
Tesfa, Lydia
Augustine, Titto A.
Klampfer, Lidija
Coffey, Matthew C.
Mariadason, John M.
Goel, Sanjay
author_sort Maitra, Radhashree
collection PubMed
description Reovirus is a double stranded RNA virus, with an intrinsic preference for replication in KRAS mutant cells. As 45% of human colorectal cancers (CRC) harbor KRAS mutations, we sought to investigate its efficacy in KRAS mutant CRC cells, and examine its impact in combination with the topoisimerase-1 inhibitor, irinotecan. Reovirus efficacy was examined in the KRAS mutant HCT116, and the isogenic KRAS WT Hke3 cell line, and in the non-malignant rat intestinal epithelial cell line. Apoptosis was determined by flow cytometry and TUNEL staining. Combination treatment with reovirus and irintoecan was investigated in 15 CRC cell lines, including the HCT116 p21 isogenic cell lines. Reovirus preferentially induced apoptosis in KRAS mutant HCT116 cells compared to its isogenic KRAS WT derivative, and in KRAS mutant IEC cells. Reovirus showed a greater degree of caspase 3 activation with PARP 1 cleavage, and preferential inhibition of p21 protein expression in KRAS mutant cells. Reovirus synergistically induced growth inhibition when combined with irinotecan. This synergy was lost upon p21 gene knock out. Reovirus preferentially induces apoptosis in KRAS mutant colon cancer cells. Reovirus and irinotecan combination therapy is synergistic, p21 mediated, and represents a novel potential treatment for patients with CRC.
format Online
Article
Text
id pubmed-4058046
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-40580462014-06-18 Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan Maitra, Radhashree Seetharam, Raviraja Tesfa, Lydia Augustine, Titto A. Klampfer, Lidija Coffey, Matthew C. Mariadason, John M. Goel, Sanjay Oncotarget Research Paper Reovirus is a double stranded RNA virus, with an intrinsic preference for replication in KRAS mutant cells. As 45% of human colorectal cancers (CRC) harbor KRAS mutations, we sought to investigate its efficacy in KRAS mutant CRC cells, and examine its impact in combination with the topoisimerase-1 inhibitor, irinotecan. Reovirus efficacy was examined in the KRAS mutant HCT116, and the isogenic KRAS WT Hke3 cell line, and in the non-malignant rat intestinal epithelial cell line. Apoptosis was determined by flow cytometry and TUNEL staining. Combination treatment with reovirus and irintoecan was investigated in 15 CRC cell lines, including the HCT116 p21 isogenic cell lines. Reovirus preferentially induced apoptosis in KRAS mutant HCT116 cells compared to its isogenic KRAS WT derivative, and in KRAS mutant IEC cells. Reovirus showed a greater degree of caspase 3 activation with PARP 1 cleavage, and preferential inhibition of p21 protein expression in KRAS mutant cells. Reovirus synergistically induced growth inhibition when combined with irinotecan. This synergy was lost upon p21 gene knock out. Reovirus preferentially induces apoptosis in KRAS mutant colon cancer cells. Reovirus and irinotecan combination therapy is synergistic, p21 mediated, and represents a novel potential treatment for patients with CRC. Impact Journals LLC 2014-04-24 /pmc/articles/PMC4058046/ /pubmed/24798549 Text en Copyright: © 2014 Maitra et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Maitra, Radhashree
Seetharam, Raviraja
Tesfa, Lydia
Augustine, Titto A.
Klampfer, Lidija
Coffey, Matthew C.
Mariadason, John M.
Goel, Sanjay
Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan
title Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan
title_full Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan
title_fullStr Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan
title_full_unstemmed Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan
title_short Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan
title_sort oncolytic reovirus preferentially induces apoptosis in kras mutant colorectal cancer cells, and synergizes with irinotecan
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058046/
https://www.ncbi.nlm.nih.gov/pubmed/24798549
work_keys_str_mv AT maitraradhashree oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan
AT seetharamraviraja oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan
AT tesfalydia oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan
AT augustinetittoa oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan
AT klampferlidija oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan
AT coffeymatthewc oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan
AT mariadasonjohnm oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan
AT goelsanjay oncolyticreoviruspreferentiallyinducesapoptosisinkrasmutantcolorectalcancercellsandsynergizeswithirinotecan