The Nrf2 inhibitor brusatol is a potent antitumour agent in an orthotopic mouse model of colorectal cancer

Jonathan P Evans,Ian M Copple,Paul A Sutton,Zhi-Xiu Lin,Daniel H Palmer,D Mark Pritchard,Robert P Jones,Eithne Costello,Christopher E Goldring,B Kevin Park,Vicky L Fretwell,Carrie A Duckworth,Boleslaw K Winiarski,Neil R Kitteringham,Lorenzo Ressel,Elizabeth M Tweedle

doi:10.18632/oncotarget.25497

Jonathan P Evans, Ian M Copple + Show 14 more

Open Access

https://doi.org/10.18632/oncotarget.25497

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Abstract

Nrf2 is a transcription factor that regulates cellular stress response and irinotecan-metabolising pathways. Its aberrant activity has been reported in a number of cancers, although relatively few studies have explored a role for Nrf2 in colorectal cancer (CRC). This study assessed the expression of Nrf2 in patient CRC tissues and explored the effect of Nrf2 modulation alone, or in combination with irinotecan, in human (HCT116) and murine (CT26) cell lines in vitro and in an orthotopic syngeneic mouse model utilising bioluminescent imaging. Using a tissue microarray, Nrf2 was found to be overexpressed (p<0.01) in primary CRC and metastatic tissue relative to normal colon, with a positive correlation between Nrf2 expression in matched primary and metastatic samples. In vitro experiments in CRC cell lines revealed that Nrf2 siRNA and brusatol, which is known to inhibit Nrf2, decreased viability and sensitised cells to irinotecan toxicity. Furthermore, brusatol effectively abrogated CRC tumour growth in subcutaneously and orthotopically-allografted mice, resulting in an average 8-fold reduction in luminescence at the study end-point (p=0.02). Our results highlight Nrf2 as a promising drug target in the treatment of CRC.

Highlights

Colorectal cancer (CRC) continues to be the second leading cause of cancer-related death in the Western World, with the worst outcomes in patients with metastatic disease [1]
We demonstrate that modulation of Nuclear factor-erythroid 2-related factor 2 (Nrf2) can sensitise colorectal cancer (CRC) cells to the cytotoxic effects of irinotecan in vitro, and that brusatol can inhibit tumour growth in a syngeneic orthotopic mouse model of CRC
There was no difference in Nrf2 expression in the primary (Figure 1D) or metastatic samples (Figure 1E) of chemonaïve patients when compared to those who received neoadjuvant chemotherapy, suggesting the observed high expression of Nrf2 was not a marker of increased cellular stress induced by chemotherapy

Summary

Introduction

Colorectal cancer (CRC) continues to be the second leading cause of cancer-related death in the Western World, with the worst outcomes in patients with metastatic disease (mCRC) [1]. Neoadjuvant chemotherapy can bring patients with mCRC to resection, while in the adjuvant setting it can treat systemic disease. First-line treatment varies with geographical location, in the US the FOLFIRI regimen (5-flurouracil, leucovorin and Irinotecan) predominates. In the UK, irinotecan-based regimens are more commonly employed in the management of patients with advanced disease who have failed with oxaliplatin based therapy. Chemotherapy-response varies significantly, disease progression is common, while debilitating side-effects or systemic toxicity can limit treatment [2]. The development of novel therapies is essential and is achieved through the identification of drug-targetable molecular pathways involved in cancer cell survival or chemo-resistance

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