New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells.,Experimental & Molecular Medicine

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New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells.
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2020-02-20 , DOI: 10.1038/s12276-020-0389-x
Begoña Alburquerque-González ₁ , Manuel Bernabé-García ₂ , Silvia Montoro-García ₃ , Ángel Bernabé-García ₄ , Priscila Campioni Rodrigues _{5,

6} , Javier Ruiz Sanz ₇ , Fernando F López-Calderón ₁ , Irene Luque ₇ , Francisco José Nicolas ₃ , María Luisa Cayuela ₄ , Tuula Salo _{5,

6,

8,

9} , Horacio Pérez-Sánchez ₁₀ , Pablo Conesa-Zamora _{1,

11,

12}

Affiliation

Pathology and Histology Department, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, 30107, Guadalupe, Murcia, Spain.
Research group "Telomerasa, Envejecimiento y Cáncer," CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.
Cell Culture Lab, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain.
Research group "Regeneración, oncología molecular y TGF-β", Institute for Biohealth Research from Murcia (IMIB), Hospital Clínico Universitario Virgen de la ArrixacaCarretera Madrid-Cartagena, El Palmar, Spain.
Cancer Research and Translational Medicine Research Unit, University of Oulu, Aapistie 5A, FI-90220, Oulu, Finland.
Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
Department of Physical Chemistry and Institute of Biotechnology, University of Granada, Campus Fuentenueva s/n, 18071, Granada, Spain.
Institute of Oral and Maxillofacial Disease, University of Helsinki, Helsinki, Finland.
HUSLAB, Department of Pathology, Helsinki University Hospital, Helsinki, Finland.
Structural Bioinformatics and High Performance Computing (BIO-HPC) Research Group, Universidad Católica de Murcia (UCAM), Guadalupe, Spain.
Clinical Analysis Department, Group of Molecular Pathology and Pharmacogenetics, Institute for Biohealth Research from Murcia (IMIB), Hospital Universitario Santa Lucía, c/Mezquita sn, 30202, Cartagena, Spain.
C/Mezquita s/n CP, 30202, Cartagena, Murcia, Spain.

Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors.

中文翻译：

抗抑郁药丙咪嗪在大肠癌细胞中作为Fascin1抑制剂的新作用。

锯齿状腺癌（SAC）较常规结肠直肠癌（CRC）具有更大的浸润性，其结局更差，其特征在于对抗表皮生长因子受体（EGFR）的频繁耐药性以及fascin1的过度表达，fascin1是肌动蛋白捆绑中起着重要作用的关键蛋白。在肿瘤侵袭中起重要作用，并且在不同类型的预后不良的癌症中过表达。在计算机上筛选了9591种化合物，包括获得美国食品药品监督管理局（FDA）批准的2037种化合物，并通过差示扫描荧光分析了所选化合物的fascin1结合亲和力。将该结果与作为典型fascin1抑制剂的偏头痛抑制素进行了比较。在计算机筛选和差示扫描荧光法中，FDA批准的抗抑郁药丙咪嗪是最明显的潜在fascin1阻滞剂。生物物理和不同的体外肌动蛋白束测定法证实了这种活性。随后使用3D人体组织调查层状脂膜形成以及结肠直肠癌细胞迁移和侵袭的测定方法证明了米帕明具有抗fascin1和抗侵袭活性。此外，表达谱分析表明丙咪嗪对肌动蛋白细胞骨架具有活性。此外，使用斑马鱼入侵模型的体内研究表明，丙咪嗪是可以耐受的，其抗侵袭和抗转移活性是剂量依赖性的，并且与组成型和诱导型fascin1表达有关。这是第一个证明丙咪嗪作为fascin1抑制剂的抗肿瘤作用，并为SAC和其他fascin1过表达的肿瘤的分子靶向治疗奠定了基础。

更新日期：2020-02-20

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