Wee1 Inhibitor AZD1775 Effectively Inhibits the Malignant Phenotypes of Esophageal Squamous Cell Carcinoma In Vitro and In Vivo

被引:16
作者
Bi, Shuning [1 ]
Wei, Qiuren [1 ]
Zhao, Zhijun [2 ]
Chen, Liang [1 ]
Wang, Chaojie [3 ]
Xie, Songqiang [1 ]
机构
[1] Henan Univ, Coll Pharm, Inst Chem Biol, Kaifeng, Peoples R China
[2] Luohe Med Coll, Dept Med & Therapeut, Luohe, Peoples R China
[3] Henan Univ, Key Lab Nat Med & Immunoengn, Kaifeng, Peoples R China
基金
中国国家自然科学基金;
关键词
ESCC; Wee1; AZD1775; apoptosis; metastasis; CANCER-CELLS; THERAPEUTIC TARGET; DNA-DAMAGE; PROMOTES TUMORIGENICITY; KINASE INHIBITOR; PHASE-II; MK-1775; METASTASIS; APOPTOSIS; AGENTS;
D O I
10.3389/fphar.2019.00864
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Esophageal squamous cell carcinoma (ESCC) is a common malignant diagnosed cancer with increasing incidence rate and few treatment options. As a specific small-molecule inhibitor of the Wee1 tyrosine kinase, AZD1775 has previously shown potent antitumor effect on multiple types of cancer in various preclinical studies and clinical trials. However, the expression of Wee1 and the role of AZD1775 in ESCC remain unclear. In the present study, we found that the expression of Wee1 was much higher in ESCC cell lines and clinical samples than that of the corresponding controls. In addition, we demonstrated that AZD1775 exhibited strong inhibitory effect against Wee1 kinase in both tested ESCC cells at nanomolar concentrations. Moreover, AZD1775 effectively suppressed ESCC cell growth and triggered apoptosis via the mitochondrial-dependent signaling pathway. AZD1775 also diminished cell migration and invasion as well as the expression of MMP-2 and MMP-9. Interestingly, knockdown of Wee1 displayed a similar inhibitory effect of AZD1775 on ESCC cells. In addition, there was a synergism between AZD1775 and 5-fluorouracil or cisplatin in inducing cell death. More importantly, the in vivo experiments also demonstrated that AZD1775 potently inhibited ESCC cell growth and metastasis. In summary, our data suggest that the Wee1 inhibitor AZD1775 may be a potential therapeutic agent and warrants a clinical trial for patients with ESCC, even those with metastasis.
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页数:16
相关论文
共 56 条
[1]   Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis [J].
Bukhari, Amirali B. ;
Lewis, Cody W. ;
Pearce, Joanna J. ;
Luong, Deandra ;
Chan, Gordon K. ;
Gamper, Armin M. .
JOURNAL OF CLINICAL INVESTIGATION, 2019, 129 (03) :1329-1344
[2]   Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis [J].
Chen, G. ;
Zhang, B. ;
Xu, H. ;
Sun, Y. ;
Shi, Y. ;
Luo, Y. ;
Jia, H. ;
Wang, F. .
ONCOGENE, 2017, 36 (50) :6863-6872
[3]   Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells [J].
Chen, Liang ;
Pan, Jingxuan .
BRITISH JOURNAL OF PHARMACOLOGY, 2017, 174 (15) :2427-2443
[4]   DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway [J].
Chen, Liang ;
Li, Ming ;
Li, Qian ;
Wang, Chao-jie ;
Xie, Song-qiang .
MOLECULAR CANCER, 2013, 12
[5]   Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method [J].
Chou, Ting-Chao .
CANCER RESEARCH, 2010, 70 (02) :440-446
[6]   A randomised phase II study of chemoradiotherapy with or without nimotuzumab in locally advanced oesophageal cancer: NICE trial [J].
de Castro Junior, Gilberto ;
Segalla, Jose Getulio ;
de Azevedo, Sergio Jobim ;
Andrade, Carlos Jose ;
Grabarz, Daniel ;
Lima Franca, Bruno de Araujo ;
Del Giglio, Auro ;
Lazaretti, Nicolas Silva ;
Alvares, Maria Nunes ;
Pedrini, Jose Luiz ;
Kussumoto, Celio ;
de Matos Neto, Joao Nunes ;
Forones, Nora Manoukian ;
Fernandes Junior, Hezio Jadir ;
Borges, Giuliano ;
Girotto, Gustavo ;
Cotrim Guerreiro da Silva, Ismael Dale ;
Maluf-Filho, Fauze ;
Skare, Nils Gunnar .
EUROPEAN JOURNAL OF CANCER, 2018, 88 :21-30
[7]   Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors [J].
Do, Khanh ;
Wilsker, Deborah ;
Ji, Jiuping ;
Zlott, Jennifer ;
Freshwater, Tomoko ;
Kinders, Robert J. ;
Collins, Jerry ;
Chen, Alice P. ;
Doroshow, James H. ;
Kummar, Shivaani .
JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (30) :3409-+
[8]   Wee1 kinase inhibitor MK-1775 induces apoptosis of acute lymphoblastic leukemia cells and enhances the efficacy of doxorubicin involving downregulation of Notch pathway [J].
Duan, Yanchao ;
Dong, Xin ;
Nie, Jing ;
Li, Peng ;
Lu, Fei ;
Ma, Daoxin ;
Ji, Chunyan .
ONCOLOGY LETTERS, 2018, 16 (04) :5473-5481
[9]   Medical progress - Esophageal cancer [J].
Enzinger, PC ;
Mayer, RJ .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (23) :2241-2252
[10]   Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation [J].
Fung, Tsun Ming ;
Ng, Kai Yu ;
Tong, Man ;
Chen, Jin-Na ;
Chai, Stella ;
Chan, Kin-Tak ;
Law, Simon ;
Lee, Nikki P. ;
Choi, Mei Yuk ;
Bin Li ;
Cheung, Annie L. ;
Tsao, Sai Wah ;
Qin, Yan-Ru ;
Guan, Xin-Yuan ;
Chan, Kwok Wah ;
Ma, Stephanie .
JOURNAL OF PATHOLOGY, 2016, 239 (03) :309-319