The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers
Ziyin Tian,
Yan Yang,
He Wu,
Yongye Chen,
Hao Jia,
Lei Zhu,
Runjia He,
Yibo Jin,
Bei Zhou,
Chunpo Ge,
Yanxia Sun,
Yun Yang
Affiliations
Ziyin Tian
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Yan Yang
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
He Wu
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Yongye Chen
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Hao Jia
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Lei Zhu
Department of Nucleus Radiation-related Injury Treatment, PLA Rocket Force Characteristic Medical Center, Beijing, China
Runjia He
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Yibo Jin
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Bei Zhou
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Chunpo Ge
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
Yanxia Sun
Department of Galactophore, The First People's Hospital of Xinxiang, Xinxiang, China; Corresponding author.
Yun Yang
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China; Henan International Joint Laboratory of Immunity and Targeted Therapy for Liver-intestinal Tumors, Xinxiang, China; Corresponding author.
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.
