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

Radhashree Maitra, Raviraja Seetharam, Lydia Tesfa, Titto A. Augustine, Lidija Klampfer, Matthew C. Coffey, John M. Mariadason, Sanjay Goel

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2807-2819
Number of pages13
JournalOncotarget
Volume5
Issue number9
StatePublished - 2014

Fingerprint

irinotecan
Colorectal Neoplasms
Apoptosis
Cell Line
HCT116 Cells
Gene Knockout Techniques
Double-Stranded RNA
RNA Viruses
In Situ Nick-End Labeling
Caspase 3
Colonic Neoplasms
Flow Cytometry
Therapeutics
Epithelial Cells
Staining and Labeling
Mutation

Keywords

  • Apoptosis
  • Caspase3
  • Colorectal cancer
  • p21
  • Reovirus

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

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.

In: Oncotarget, Vol. 5, No. 9, 2014, p. 2807-2819.

Research output: Contribution to journalArticle

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AU - Klampfer, Lidija

AU - Coffey, Matthew C.

AU - Mariadason, John M.

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