BI-847325, a selective dual MEK and Aurora kinases inhibitor, reduces aggressive behavior of anaplastic thyroid carcinoma on an in vitro three-dimensional culture

Cancer Cell International

Research

Parviz Fallah¹  Mahmood Naderi²  Alireza Naderi Sohi³  Maryam Amini Shirkouhi³  Hilda Samimi⁴  Vahid Haghpanah⁵  Rezvan Tavakoli⁶ 

[1] Department of Laboratory Science, Faculty of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran;Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran;Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran;Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran;Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran;Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran;Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran;Hepatitis and HIV Department, Pasteur Institute of Iran, Tehran, Iran;

关键词: Anaplastic thyroid carcinoma;    BI-847325;    MEK;    Aurora kinase;   

DOI  :  10.1186/s12935-022-02813-6

 received in 2022-09-14, accepted in 2022-11-28,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAnaplastic thyroid carcinoma (ATC) is the most aggressive subtype of thyroid cancer. In this study, we used a three-dimensional in vitro system to evaluate the effect of a dual MEK/Aurora kinase inhibitor, BI-847325 anticancer drug, on several cellular and molecular processes involved in cancer progression.MethodsHuman ATC cell lines, C643 and SW1736, were grown in alginate hydrogel and treated with IC50 values of BI-847325. The effect of BI-847325 on inhibition of kinases function of MEK1/2 and Aurora kinase B (AURKB) was evaluated via Western blot analysis of phospho-ERK1/2 and phospho-Histone H3 levels. Sodium/iodide symporter (NIS) and thyroglobulin (Tg), as two thyroid-specific differentiation markers, were measured by qRT-PCR as well as flow cytometry and immunoradiometric assay. Apoptosis was assessed by Annexin V/PI flow cytometry and BIM, NFκB1, and NFκB2 expressions. Cell cycle distribution and proliferation were determined via P16, AURKA, and AURKB expressions as well as PI and CFSE flow cytometry assays. Multidrug resistance was evaluated by examining the expression of MDR1 and MRP1. Angiogenesis and invasion were investigated by VEGF expression and F-actin labeling with Alexa Fluor 549 Phalloidin.ResultsWestern blot results showed that BI-847325 inhibits MEK1/2 and AURKB functions by decreasing phospho-ERK1/2 and phospho-Histone H3 levels. BI-847325 induced thyroid differentiation markers and apoptosis in ATC cell lines. Inversely, BI-847325 intervention decreased multidrug resistance, cell cycle progression, proliferation, angiogenesis, and invasion at the molecular and/or cellular levels.ConclusionThe results of the present study suggest that BI-857,325 might be an effective multi-targeted anticancer drug for ATC treatment.

【 授权许可】

CC BY   
© The Author(s) 2022

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