Anti-Anaplastic Thyroid Cancer (ATC) Effects and Mechanisms of PLX3397 (Pexidartinib), a Multi-Targeted Tyrosine Kinase Inhibitor (TKI)

被引:4
|
作者
Luo, Jingtao [1 ,2 ,3 ,4 ]
Wang, Yun [1 ,2 ,3 ,4 ]
Zhao, Lingkun [1 ,2 ,3 ,4 ]
Wang, Chunli [1 ,2 ,3 ,4 ]
Zhang, Ze [1 ,2 ,3 ,4 ]
机构
[1] Tianjin Med Univ, Natl Clin Res Ctr Canc, Dept Maxillofacial & Otorhinolaryngol Oncol, Canc Inst & Hosp, Tianjin 300060, Peoples R China
[2] Tianjin Med Univ, Natl Clin Res Ctr Canc, Dept Head & Neck Oncol, Canc Inst & Hosp, Tianjin 300060, Peoples R China
[3] Tianjins Clin Res Ctr Canc, Tianjin 300060, Peoples R China
[4] Key Lab Canc Prevent & Therapy, Tianjin 300060, Peoples R China
基金
中国国家自然科学基金;
关键词
PLX3397 (Pexidartinib); anaplastic thyroid cancer (ATC); reactive oxygen species (ROS); endoplasmic reticulum (ER) stress; Nrf2; SIGNALING PATHWAY; INDUCED APOPTOSIS; ER STRESS; ROS; NRF2; ACTIVATION; BLOCKADE; ROLES;
D O I
10.3390/cancers15010172
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary Anaplastic thyroid cancer (ATC) is the highest lethal type of thyroid cancer. Regrettably, ATC patients respond poorly to multiple treatment strategies. Therefore, there is imperative to strengthen the therapeutic approach to this vicious form of cancer. In the present study, we found that pexidartinib induces ER stress and elevated ROS in ATC cells. The apoptotic cells, and ER stress in ATC after administration of pexidartinib could be reversed by ER stress inhibitor and ROS scavenger, respectively. Furthermore, pexidartinib treatment induced Nrf2 (Nuclear Factor Erythroid 2-related Factor 2) accumulation in nuclei and reduced the interaction of Nrf2 with Keap-1 (Kelch-like ECH-associated protein 1), while the knockdown of Nrf2 enhanced the anti-ATC effects of pexidartinib in vitro. In addition, pexidartinib significantly inhibits ATC xenografts growth and proliferation in vivo, and the combination of ML385, an Nrf2 inhibitor, potently enhanced the anti-ATC effects of pexidartinib in vivo. Our findings suggest pexidartinib to be a potential agent for treating of ATC. Background Anaplastic thyroid cancer (ATC) is the greatest lethal thyroid neoplasm with a low incidence and lacks an effective treatment strategy and standardized treatment protocol. PLX3397 (Pexidartinib) is an FDA-approved multitarget tyrosine kinase inhibitor. The research is designed to explore the possible anti-proliferative activity of pexidartinib on ATC, as well as its related molecular mechanisms. Methods The cell viability was assessed by CCK-8, LDH release, colony formation, and EdU detection assays. Apoptosis and the alteration on cell cycle arrest were characterized by flow cytometry (FCM). ER stress was evaluated by immunofluorescence (IF). ROS levels were determined by flow cytometry. Western blot assays were conducted to evaluate changes in key molecules related to apoptosis and ER stress. The ATC xenografts model was established, and immunohistochemistry was performed to validate the anti-ATC effects of pexidartinib in vivo. Results Pexidartinib significantly inhibited ATC cell proliferation and induced apoptosis and cell cycle arrest. Moreover, pexidartinib potently induced ER stress and elevated ROS in ATC cells, and the apoptotic cells and ER stress in ATC after administration of pexidartinib could be reversed by an ER stress inhibitor and ROS scavenger, respectively. Furthermore, pexidartinib treatment induced Nrf2 accumulation in nuclei and reduced the interaction of Nrf2 with Keap-1, and knockdown of Nrf2 enhanced the anti-ATC effects of pexidartinib in vitro. In addition, pexidartinib significantly inhibited ATC xenograft growth and proliferation in vivo, and the combination of ML385, an Nrf2 inhibitor, potently enhanced the anti-ATC effects of pexidartinib in vivo. Conclusion Our findings suggest pexidartinib is a potential agent for treating ATC. Co-administration with an Nrf2 inhibitor is an effective synergistic strategy.
引用
收藏
页数:15
相关论文
共 27 条
  • [1] TKI258, a novel, multi-targeted tyrosine kinase inhibitor for the treatment of breast cancer
    Liu, Hongyu
    Dieing, Annette
    Lehenbauer-Dehm, Sylvia
    Kuehnhardt, Dagmar
    Regierer, Anne
    Schulz, Carsten
    Storek, Benjamin
    Schwarck, Sandra
    Possinger, Kurt
    Eucker, Jan
    CANCER RESEARCH, 2009, 69
  • [2] A novel selective multi-targeted tyrosine kinase inhibitor with superior anti-tumor efficacy
    Hjarnaa, P.
    Fensholdt, Jef
    INFLAMMATION RESEARCH, 2007, 56 : S464 - S465
  • [4] Multi-targeted tyrosine kinase inhibitor Cabozantinib as a therapeutic agent in MET-overexpressing gastric cancer
    Choi, Audrey H.
    Lu, Jianming
    Lee, Sangjun
    Chu, Peiguo
    Chung, Vincent
    Lin, Ren-Jang
    Kim, Joseph
    Chao, Joseph
    CANCER RESEARCH, 2015, 75
  • [5] Effects of a multi-targeted receptor tyrosine kinase inhibitor on radiosentization of head and neck squamous cell carcinoma
    Mirshahidi, Saied
    Hsu, Heng-Wei
    Chen, Chien-Shing
    JOURNAL OF IMMUNOLOGY, 2012, 188
  • [6] Anti-tumoral effects of the multi-targeted kinase inhibitor AEE788 in BRAF mutated colorectal cancer cells
    Valverde, A.
    Gomez-Espana, A.
    Hernandez, V.
    Jimenez, J.
    Lopez-Sanchez, L. M.
    Cano, M. T.
    De la Haba-Rodriguez, J. R.
    Lopez-Pedrera, C.
    Rodriguez-Ariza, A.
    Aranda, E.
    EJC SUPPLEMENTS, 2010, 8 (07): : 71 - 71
  • [7] The effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, against human U87 malignant glioblastoma cells
    Zhang, Junxia
    Zhou, Qiang
    Gao, Ge
    Wang, Yanfen
    Fang, Zhihui
    Li, Guanlin
    Yu, Mengfei
    Kong, Lingfei
    Xing, Ying
    Gao, Xiaoqun
    ONCOTARGETS AND THERAPY, 2014, 7 : 2013 - 2019
  • [8] THE MULTI-TARGETED KINASE INHIBITOR AEE788 EXERTS ANTI-PROLIFERATIVE EFFECTS IN BRAF MUTATED COLORECTAL CANCER CELLS
    Valverde, A.
    Gomez-Espana, A.
    Hernandez, V.
    Jimenez, J.
    Lopez-Sanchez, L. M.
    Cano, M. T.
    De La Haba-Rodriguez, J. R.
    Lopez-Pedrera, C.
    Rodriguez-Ariza, A.
    Aranda, E.
    ANNALS OF ONCOLOGY, 2010, 21 : 190 - 191
  • [9] The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells
    Zhou, Yan
    Zhang, Yuanliang
    Zou, Hanbing
    Cai, Ning
    Chen, Xiaojing
    Xu, Longmei
    Kong, Xianming
    Liu, Peifeng
    SCIENTIFIC REPORTS, 2015, 5
  • [10] The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells
    Yan Zhou
    Yuanliang Zhang
    Hanbing Zou
    Ning Cai
    Xiaojing Chen
    Longmei Xu
    Xianming Kong
    Peifeng Liu
    Scientific Reports, 5