A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells
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- 作者：Chongchong Tian ; Pingping Ding ; Ziqiao Yuan ; Han Li ; Yanxia Zhao ; Lan Sun…
- 关键词：HER2 ; KU004 ; Cell cycle arrest ; Apoptosis
- 刊名：Apoptosis
- 出版年：2015
- 出版时间：December 2015
- 年：2015
- 卷：20
- 期：12
- 页码：1599-1612
- 全文大小：6,070 KB
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Pingping Ding (1)
Ziqiao Yuan (1)
Han Li (1)
Yanxia Zhao (1)
Lan Sun (2) (3)
Qingming Guo (2) (3)
Zhenzhong Wang (2) (3)
Lixin Sun (1) (4)
Luyong Zhang (1) (4) (5)
Zhenzhou Jiang (1) (6) (7)
1. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China
2. Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, Jiangsu, China
3. State Key Laboratory of Pharmaceutical Process New-tech for Chinese Medicine, Lianyungang, 222001, Jiangsu, China
4. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China
5. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
6. Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
7. Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China - 刊物类别：Medicine
- 刊物主题：Medicine & Public Health
Oncology
Cancer Research
Cell Biology
Biochemistry
Virology - 出版者：Springer Netherlands
- ISSN：1573-675X
文摘
Human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in cancer therapy, and HER2 protein-tyrosine kinase inhibitors have attracted considerable attention in the field of searching for novel anticancer drug candidates. In this study, we investigated the anticancer effect of KU004, a novel dual EGFR and HER2 inhibitor in vitro and in vivo. In vitro, KU004 preferentially inhibited the growth of HER2-overexpressing breast and gastric cell lines and HER2 expression level significantly correlated with response to KU004. It blocked activation of EGFR, HER2 and downstream Akt and Erk and induced G0/G1 arrest which was associated with downregulation of p53, p21, cyclin D1 and CDK4 along with increase of p27 and dephosphorylation of pRb. Apoptosis occurred in a caspase-dependent manner mainly via the extrinsic apoptotic pathway after KU004 treatment. The in vitro efficacy of KU004 was comparable to that of lapatinib. Moreover, KU004 suppressed the growth of NCI-N87 tumor and induced apoptosis without causing apparent weight loss or obvious toxicity. Tumor volume was significantly smaller in KU004-treated group than that in lapatinib-treated group at comparable dose levels. Taken together, these findings demonstrate KU004 can be expected to be a promising anti-HER2 candidate. Keywords HER2 KU004 Cell cycle arrest Apoptosis