Brusatol Enhances the Chemotherapy Efficacy of Gemcitabine in Pancreatic Cancer via the Nrf2 Signalling Pathway

Abstract

Although gemcitabine is the standard chemotherapy treatment for advanced pancreatic cancer, its benefits are quite limited due to prevalent chemoresistance, and the mechanism underlying gemcitabine chemoresistance remains unclear. Currently, Nrf2 has been deemed as a significant contributor to gemcitabine chemoresistance in pancreatic cancer. Brusatol is a unique inhibitor of the Nrf2 pathway, and in previous studies, we determined that brusatol exhibits the effects of growth inhibition and proapoptosis in pancreatic cancer cells. Due to these data, we speculate that brusatol can reverse gemcitabine-induced Nrf2 activation and propose that it can enhance gemcitabine efficacy in treating pancreatic cancer. In this study, we first proved that brusatol can effectively inhibit the Nrf2 signalling pathway and increase ROS accumulation in pancreatic cancer cells. Next, we demonstrated that brusatol can abrogate gemcitabine-induced Nrf2 activation in pancreatic cancer cells. In addition, we discovered that brusatol potentiates gemcitabine-induced growth inhibition and apoptosis in human pancreatic cancer cells. In nude mice with PANC-1 xenografts, treatment with a combination of brusatol and gemcitabine considerably reduced in vivo tumour growth compared with control treatment or treatment with either brusatol or gemcitabine alone. Immunohistochemical staining also showed that Nrf2 expression levels were reduced in brusatol-treated xenograft tumour tissues. In summary, our results suggest that brusatol is capable of enhancing the antitumour effects of gemcitabine in both pancreatic cancer cells and PANC-1 xenografts via suppressing the Nrf2 pathway.

RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

“…The vital roles of NRF2 in radiotherapy resistance have been well announced in a plethora of studies 5 . For example, downregulation of NRF2 is the main reason for the radiosensitive agents, such as cordycepin 41 , valproic acid 42 , and brusatol 43 . The radiosensitive ability of salinomycin also depends on inhibition of NRF2 in NPC cells 17 , suggesting NRF2 involves in regulating of NPC radioresistance as well.…”

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Here, Brusatol induced ROS accumulation, growth inhibition and apoptosis by decreasing the protein levels of NRF2 and its target genes HO-1 and NQO-1. Notably, Brusatol enhanced the antitumor activity of Gemcitabine in vivo by reducing the growth rate of PANC-1 xenografts implanted in BALB/c nude mice [315]. Similarly, other work has been directed to Halofuginone from the plant Dichroa febrifuga, which is rapidly emerging as one of the most promising NRF2 inhibitors.…”

Nrf2 Inhibitor, Brusatol in Combination with Trastuzumab Exerts Synergistic Antitumor Activity in HER2-Positive Cancers by Inhibiting Nrf2/HO-1 and HER2-AKT/ERK1/2 Pathways

“…Brusatol, as a unique Nrf2 inhibitor, has recently been shown to regress tumor burden through inhibiting Nrf2 signaling in several tumor models [31,32,42]. More importantly, brusatol exhibits the potential as an adjuvant drug to enhance the efficacy of chemotherapeutic such as gemcitabine or cisplatin in pancreatic cancer or lung cancer [31,34]. In the study, we firstly found that brusatol was a potent antitumor compound against HER2-positive cancer cells.…”

“…Oxygen Species (ROS) Accumulation and Apoptosis in BT-474 and SK-OV-3 Cancer Cells. Nrf2 suppression always caused elevation of ROS and subsequently resulted in apoptosis [34,38,39]. Next, we examined the level of ROS accumulation when BT-474 and SK-OV-3 cells were exposed to brusatol.…”

“…Wu et al revealed that brusatol has the capacity to decrease the Nrf2 expression level and enhanced the cytotoxicity of Taxol [ 33 ]. Xiang et al showed that brusatol effectively enhances the anticancer effects of gemcitabine through inhibiting gemcitabine-induced Nrf2 activation in pancreatic cancers [ 34 ]. Also, brusatol shows the potency on enhancing the toxicity of irinotecan and inducing cell death in human colon cancer cells [ 35 ].…”