Indolyl-chalcone derivatives trigger apoptosis in cisplatin-resistant mesothelioma cells through aberrant tubulin polymerization and deregulation of microtubule-associated proteins

Frontiers in Oncology

Oncology

Julia Schüler¹  German Ott²  Heike Horn³  Claudia Kalla³  Sophia Steinlein³  Lijun Sun⁴  Amanda Franceschini Ghilardi⁴  Angelika Hausser⁵  Frank Essmann⁶ 

[1] Charles River Germany GmbH, Freiburg, Germany;Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany;Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany;Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany;Department of Clinical Pharmacology, University Hospital, University of Tuebingen, Tuebingen, Germany;Harvard Medical School, Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, United States;Institute of Cell Biology and Immunology and Stuttgart Research Center for Systems Biology, University of Stuttgart, Stuttgart, Germany;Robert Bosch Center for Tumor Diseases, Stuttgart, Germany;

关键词: indolyl-chalcone;    CIT-026;    CIT-223;    apoptosis;    microtubules;    stathmin;    cisplatin resistance;    pleural mesothelioma;   

DOI  :  10.3389/fonc.2023.1190988

 received in 2023-03-21, accepted in 2023-05-11,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionMalignant pleural mesothelioma (MPM) is a neoplasm with dismal prognosis and notorious resistance to the standard therapeutics cisplatin and pemetrexed. Chalcone derivatives are efficacious anti-cancer agents with minimal toxicity and have, therefore, gained pharmaceutical interest. Here, we investigated the efficacy of CIT-026 and CIT-223, two indolyl-chalcones (CITs), to inhibit growth and viability of MPM cells and defined the mechanism by which the compounds induce cell death.MethodsThe effects of CIT-026 and CIT-223 were analyzed in five MPM cell lines, using viability, immunofluorescence, real-time cell death monitoring, and tubulin polymerization assays, along with siRNA knockdown. Phospho-kinase arrays and immunoblotting were used to identify signaling molecules that contribute to cell death.ResultsCIT-026 and CIT-223 were toxic in all cell lines at sub-micromolar concentrations, in particular in MPM cells resistant to cisplatin and pemetrexed, while normal fibroblasts were only modestly affected. Both CITs targeted tubulin polymerization via (1) direct interaction with tubulin and (2) phosphorylation of microtubule regulators STMN1, CRMP2 and WNK1. Formation of aberrant tubulin fibers caused abnormal spindle morphology, mitotic arrest and apoptosis. CIT activity was not reduced in CRMP2-negative and STMN1-silenced MPM cells, indicating that direct tubulin targeting is sufficient for toxic effects of CITs.DiscussionCIT-026 and CIT-223 are highly effective inducers of tumor cell apoptosis by disrupting microtubule assembly, with only modest effects on non-malignant cells. CITs are potent anti-tumor agents against MPM cells, in particular cells resistant to standard therapeutics, and thus warrant further evaluation as potential small-molecule therapeutics in MPM.

【 授权许可】

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Copyright © 2023 Steinlein, Essmann, Ghilardi, Horn, Schüler, Hausser, Sun, Ott and Kalla