Identification of the atypical antipsychotic Asenapine as a direct survivin inhibitor with anticancer properties and sensitizing effects to conventional therapies.

Autor: Benítez-García C; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Molecular Signaling, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain., Martínez-García D; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Molecular Signaling, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain., Kotev M; Nostrum Biodiscovery, Av. de Josep Tarradellas, 8-10, Barcelona E-08029, Spain., Pérez-Hernández M; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Molecular Signaling, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain., Westermaier Y; Nostrum Biodiscovery, Av. de Josep Tarradellas, 8-10, Barcelona E-08029, Spain., Díaz L; Nostrum Biodiscovery, Av. de Josep Tarradellas, 8-10, Barcelona E-08029, Spain., Korrodi-Gregório L; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain., Fontova P; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Department of Chemistry, Universidad de Burgos, Burgos, Spain., Torres AA; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Molecular Signaling, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain., Pérez-Tomás R; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain., García-Valverde M; Department of Chemistry, Universidad de Burgos, Burgos, Spain., Quesada R; Department of Chemistry, Universidad de Burgos, Burgos, Spain., Soliva R; Nostrum Biodiscovery, Av. de Josep Tarradellas, 8-10, Barcelona E-08029, Spain., Soto-Cerrato V; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Molecular Signaling, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain. Electronic address: vsoto@ub.edu.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Dec 17; Vol. 182, pp. 117756. Date of Electronic Publication: 2024 Dec 17.
DOI: 10.1016/j.biopha.2024.117756
Abstrakt: Therapy resistance in human cancers is a major limitation in Clinical Oncology. In this regard, overexpression of anti-apoptotic proteins, such as survivin, has been described in several tumors, contributing to this clinical issue. Survivin has a dual role in key cellular functions, inducing cell cycle progression and inhibiting apoptosis; thus, survivin is an attractive target for cancer therapy. Therefore, we focused on identifying and validating a novel specific, directly binding survivin inhibitor for cancer treatment and tumor sensitization to conventional proapoptotic therapies. In this work, we conducted a structure-based high-throughput virtual screening at the survivin homodimerization domain. Asenapine Maleate (AM), an approved drug for central nervous system diseases, was identified as a direct binder of the survivin homodimerization domain and it significantly affected cell viability of lung, colon, and brain cancer cell lines. Direct interaction of AM to survivin protein was corroborated by surface plasmon resonance and a specific survivin protein decrease was observed in cancer cells, compared to other inhibitors of apoptosis proteins. Therapeutic in vivo studies showed an impairment of tumor growth in AM-treated mice. Finally, a synergistic anticancer effect was detected in vitro when combined with different conventional chemotherapies, and in vivo studies showed higher antitumor effects when combined with cisplatin. Altogether, our results identify AM as a specific direct binding inhibitor of survivin, showing anticancer properties in vitro and in vivo and sensitizing effects when combined with cisplatin, opening the possibility of repositioning this approved drug for cancer treatment.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper Vanessa Soto-Cerrato and other co-authors had patent #PCT/EP2022/071374 pending to none (no longer in force). Co-author currently employed by Nostrum Biodiscovery (as mentioned in her affiliation): LD Co-author previously employed by Nostrum Biodiscovery (as mentioned in her/his affiliation): YW, RS. Therefore, there are no conflict of interests. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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