Xiaolin Peng1,2, Yao Liu1,2, Shan Zhu1, Xin Peng1, Hui Li1, Wenhui Jiao1, Peng Lin2, Zhe Zhang1, Yuling Qiu1, Meihua Jin1, Ran Wang3, Dexin Kong4,5. 1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China. 2. Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, 300192, Tianjin, China. 3. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China. wangran@tmu.edu.cn. 4. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China. kongdexin@tmu.edu.cn. 5. School of Medicine, Tianjin Tianshi College, Tianyuan University, 301700, Tianjin, China. kongdexin@tmu.edu.cn.
Abstract
PURPOSE: The present study aims to determine whether co-targeting PI3K/Akt and MAPK/ERK pathways in human hypopharyngeal squamous cell carcinoma (HSCC) is a potential anticancer strategy. METHODS: We retrospectively analyzed the clinical data of HSCC patients, and the phosphorylation status of Akt and Erk in HSCC and tumor adjacent tissues was evaluated by immunohistochemistry. MTT and colony formation assay were performed to determine the anti-proliferative effect of PI3K/mTOR inhibitor GDC-0980 and MEK inhibitor Refametinib on HSCC cell line Fadu. Wound-healing and Transwell migration assay were used to analyze the anti-migrative capability of the two drugs. The involved anti-tumor mechanism was explored by flow cytometry, qRT-PCR and western blot. The combinational anticancer effect of GDC-0980 and Refametinib was evaluated according to Chou and Talalay's method. RESULTS: The levels of p-Akt and p-Erk were increased significantly with the progression of clinical stage of HSCC, suggesting PI3K/Akt and MAPK/ERK pathways might be associated with HSCC occurrence and progression. Furthermore, both GDC-0980 and Refametinib showed obvious antitumor effects on FaDu cells. Treatment by the two drugs arrested FaDu cell cycle progression in G1 phase, with reduction of cyclin D1 and p-Rb, in contrast to enhancement of p27. GDC-0980 inhibited FaDu cell migration and reduced metastasis related proteins including p-PKCζ, p-Integrin β1 and uPA. Combination use of GDC-0980 and Refametinib exhibited strong synergistic anti-tumor effect. CONCLUSION: Dual inhibition of PI3K/Akt and MAPK/ERK pathway by GDC-0980 and Refametinib might be a promising treatment strategy for HSCC patients.
PURPOSE: The present study aims to determine whether co-targeting PI3K/Akt and MAPK/ERK pathways in humanhypopharyngeal squamous cell carcinoma (HSCC) is a potential anticancer strategy. METHODS: We retrospectively analyzed the clinical data of HSCCpatients, and the phosphorylation status of Akt and Erk in HSCC and tumor adjacent tissues was evaluated by immunohistochemistry. MTT and colony formation assay were performed to determine the anti-proliferative effect of PI3K/mTOR inhibitor GDC-0980 and MEK inhibitor Refametinib on HSCC cell line Fadu. Wound-healing and Transwell migration assay were used to analyze the anti-migrative capability of the two drugs. The involved anti-tumor mechanism was explored by flow cytometry, qRT-PCR and western blot. The combinational anticancer effect of GDC-0980 and Refametinib was evaluated according to Chou and Talalay's method. RESULTS: The levels of p-Akt and p-Erk were increased significantly with the progression of clinical stage of HSCC, suggesting PI3K/Akt and MAPK/ERK pathways might be associated with HSCC occurrence and progression. Furthermore, both GDC-0980 and Refametinib showed obvious antitumor effects on FaDu cells. Treatment by the two drugs arrested FaDu cell cycle progression in G1 phase, with reduction of cyclin D1 and p-Rb, in contrast to enhancement of p27. GDC-0980 inhibited FaDu cell migration and reduced metastasis related proteins including p-PKCζ, p-Integrin β1 and uPA. Combination use of GDC-0980 and Refametinib exhibited strong synergistic anti-tumor effect. CONCLUSION: Dual inhibition of PI3K/Akt and MAPK/ERK pathway by GDC-0980 and Refametinib might be a promising treatment strategy for HSCCpatients.
Authors: Phoebe Kuo; Julie A Sosa; Barbara A Burtness; Zain A Husain; Saral Mehra; Sanziana A Roman; Wendell G Yarbrough; Benjamin L Judson Journal: Cancer Date: 2016-03-28 Impact factor: 6.860
Authors: Marcian E Van Dort; Youngsoon Jang; Christopher A Bonham; Kevin Heist; Dilrukshika S W Palagama; Lucas McDonald; Edward Z Zhang; Thomas L Chenevert; Gary D Luker; Brian D Ross Journal: Eur J Med Chem Date: 2021-11-14 Impact factor: 6.514
Authors: Hoi-Lam Ngan; Chun-Ho Law; Yannie Chung Yan Choi; Jenny Yu-Sum Chan; Vivian Wai Yan Lui Journal: NPJ Genom Med Date: 2022-03-16 Impact factor: 6.083
Authors: Kelly L Hamilton; Stephanie A Sheehan; Edward P Retzbach; Clinton A Timmerman; Garret B Gianneschi; Patrick J Tempera; Premalatha Balachandran; Gary S Goldberg Journal: J Cancer Res Clin Oncol Date: 2020-11-17 Impact factor: 4.553
Authors: Ana Portelinha; Scott Thompson; Roger A Smith; Mariana Da Silva Ferreira; Zahra Asgari; Andrea Knezevic; Venkatraman Seshan; Elisa de Stanchina; Sandeep Gupta; Louis Denis; Anas Younes; Sanjeeva Reddy Journal: Cell Rep Med Date: 2021-07-21