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

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.

Brusatol inhibits amyloid‐β‐induced neurotoxicity in U‐251 cells via regulating the Nrf2/HO‐1 pathway

“…Similarly, a comprehensive antitumor effect of BR, through the inhibition of cell viability and the promotion of apoptosis caused by autophagy, was identified in hepatocellular carcinoma . Furthermore, many previous studies have shown that BR functions as a tumor suppressor through the involvement of the Nrf2/HO‐1 pathway . In the present study, BR regulated the Nrf2/HO‐1 pathway to inhibit neurotoxicity in U‐251 cells.…”

Potential Applications of NRF2 Inhibitors in Cancer Therapy

“…In this regard, by using tissue microarrays, Evans and coworkers found that NRF2 was highly expressed in primary CRC and metastatic tissues compared to normal colon. Here, siRNAs against NRF2 or Brusatol were found to induce cell death in human (HCT116) and murine (CT26) cell lines, enhancing also the toxicity of Irinotecan, while Brusatol potently abrogated CRC tumor growth in subcutaneously and orthotopically allografted syngeneic mice [290] (see Table 1). In another very recent study, the cotreatment with Brusatol and UVA led to the inhibition of A375 melanoma cell proliferation triggering ROS-dependent apoptosis.…”

Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer

“…Other researchers took advantage of global repressors of protein synthesis such as brusatol or halofuginone to facilitate NRF2 degradation and prevent the refilling of its intracellular content at the post-transcriptional level in solid and hematologic tumors. By doing so, potent tumor suppressive effects and enhanced chemosensitivity largely derived by overwhelming ROS accumulation, were observed in pancreatic cancer cells [ 109 ], colorectal cancer cells [ 110 ], acute myeloid leukemia (AML) cells [ 111 ], and non-small cell lung cancer (NSCLC) cells [ 112 ]. Of note, halofuginone bromide is currently under phase-1 evaluation in a clinical trial conducted on patients with advanced solid tumors (NCT00027677).…”