The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers
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 g...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S240584402201698X |
| _version_ | 1818472720406413312 |
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| author | Ziyin Tian Yan Yang He Wu Yongye Chen Hao Jia Lei Zhu Runjia He Yibo Jin Bei Zhou Chunpo Ge Yanxia Sun Yun Yang |
| author_facet | Ziyin Tian Yan Yang He Wu Yongye Chen Hao Jia Lei Zhu Runjia He Yibo Jin Bei Zhou Chunpo Ge Yanxia Sun Yun Yang |
| author_sort | Ziyin Tian |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T04:12:34Z |
| format | Article |
| id | doaj.art-0cda42353b374491acc3d881568451cc |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-14T04:12:34Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-0cda42353b374491acc3d881568451cc2022-12-22T02:13:04ZengElsevierHeliyon2405-84402022-08-0188e10410The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancersZiyin Tian0Yan Yang1He Wu2Yongye Chen3Hao Jia4Lei Zhu5Runjia He6Yibo Jin7Bei Zhou8Chunpo Ge9Yanxia Sun10Yun Yang11School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaDepartment of Nucleus Radiation-related Injury Treatment, PLA Rocket Force Characteristic Medical Center, Beijing, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaDepartment of Galactophore, The First People's Hospital of Xinxiang, Xinxiang, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S240584402201698XNrf2BrusatolLapatinibHER2ROSERK1/2 |
| spellingShingle | Ziyin Tian Yan Yang He Wu Yongye Chen Hao Jia Lei Zhu Runjia He Yibo Jin Bei Zhou Chunpo Ge Yanxia Sun Yun Yang The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers Heliyon Nrf2 Brusatol Lapatinib HER2 ROS ERK1/2 |
| title | The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers |
| title_full | The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers |
| title_fullStr | The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers |
| title_full_unstemmed | The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers |
| title_short | The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers |
| title_sort | nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in her2 positive cancers |
| topic | Nrf2 Brusatol Lapatinib HER2 ROS ERK1/2 |
| url | http://www.sciencedirect.com/science/article/pii/S240584402201698X |
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