The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers. Issue 8 (August 2022)

• Record Type: Journal Article
• Authors: Tian, Ziyin; Yang, Yan; Wu, He; Chen, Yongye; Jia, Hao; Zhu, Lei; He, Runjia; Jin, Yibo; Zhou, Bei; Ge, Chunpo; Sun, Yanxia; Yang, Yun
• Is Part Of: Heliyon. Volume 8:Issue 8(2022)
• Publication Date: 2022-08
• Subjects: Nrf2 -- Brusatol -- Lapatinib -- HER2 -- ROS -- ERK1/2 -- AKT; Research -- Periodicals; Medical sciences -- Periodicals; Natural history -- Periodicals; Social sciences -- Periodicals; Earth sciences -- Periodicals; Physical sciences -- Periodicals; 507.2
• DOI: 10.1016/j.heliyon.2022.e10410
• Languages: English
• ISSNs: 2405-8440

Abstract

Abstract: The dual tyrosine kinase (EGFR/HER2) inhibitor lapatinib is currently used to clinically treat HER2-positive breast cancer. However, a majority of patients do not respond to lapatinib therapy within 6 months. Therefore, potentiating the anti-tumor effect of lapatinib by combination treatment has a great potential to overcome the obstacle. Herein, we aim to investigate the anti-tumor activity of lapatinib in combination with brusatol and explore the potential mechanism involved in the combinatorial treatment. Our findings revealed that the Nrf2 inhibitor brusatol potently enhanced the anti-tumor effect of lapatinib against SK-BR-3, SK-OV-3 and AU565 cancer cells in a synergistic manner. Furthermore, we found that lapatinib plus brusatol more effectively decreased Nrf2 level and induced ROS generation in both SK-BR-3 and SK-OV-3 cells. Moreover, we also observed a significant reduction on the phosphorylation of HER2, EGFR, AKT and ERK1/2 in SK-BR-3 and SK-OV-3 cells when treated with lapatinib plus brusatol compared to either agent alone. More importantly, brusatol significantly augmented the anti-tumor effects of lapatinib in the SK-OV-3 xenograft model. In summary, these data provide a potential rationale for the combination of brusatol and lapatinib on the treatment of HER2-positive cancers. Abstract : Nrf2; Brusatol; Lapatinib; HER2; ROS; ERK1/2; AKT.