The HER2-targeting antibody
trastuzumab has shown effectiveness in treating HER2-positive breast and
gastric cancers; however, its responses are limited. Currently, Nrf2 has been deemed as a key
transcription factor in promoting
cancer progression and resistance by crosstalk with other proliferative signaling pathways.
Brusatol as a novel Nrf2 inhibitor has been deemed as an efficacious and safe
drug candidate in
cancer therapy. In this study, we firstly reported that
brusatol exerted the growth-inhibitory effects on HER2-positive
cancer cells by regressing Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways in these cells. More importantly, we found that
brusatol synergistically enhanced the antitumor activity of
trastuzumab against HER2-positive SK-OV-3 and BT-474 cells, which may be attributed to the inhibition of Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways. Furthermore, the synergistic effects were also observed in BT-474 and SK-OV-3
tumor xenografts. In addition, our results showed that
trastuzumab markedly enhanced
brusatol-induced ROS accumulation and apoptosis level, which could further explain the synergistic effects. To conclude, the study provided a new insight on exploring Nrf2 inhibition in combination with HER2-targeted
trastuzumab as a potential clinical treatment regimen in treating HER2-positive
cancers.