A drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells

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dc.authoridComert Onder, Ferah/0000-0002-4037-1979
dc.contributor.authorAbusharkh, Khaled A. N.
dc.contributor.authorOnder, Ferah Comert
dc.contributor.authorCinar, Venhar
dc.contributor.authorHamurcu, Zuhal
dc.contributor.authorOzpolat, Bulent
dc.contributor.authorAy, Mehmet
dc.date.accessioned2025-01-27T21:03:36Z
dc.date.available2025-01-27T21:03:36Z
dc.date.issued2024
dc.departmentÇanakkale Onsekiz Mart Üniversitesi
dc.description.abstractFOXM1, a proto-oncogenic transcription factor, plays a critical role in cancer development and treatment resistance in cancers, particularly in breast cancer. Thus, this study aimed to identify potential FOXM1 inhibitors through computational screening of drug databases, followed by in vitro validation of their inhibitory activity against breast cancer cells. In silico studies involved pharmacophore modeling using the FOXM1 inhibitor, FDI-6, followed by virtual screening of DrugBank and Selleckchem databases. The selected drugs were prepared for molecular docking, and the crystal structure of FOXM1 was pre-processed for docking simulations. In vitro studies included MTT assays to assess cytotoxicity, and Western blot analysis to evaluate protein expression levels. Our study identified Pantoprazole and Rabeprazole as potential FOXM1 inhibitors through in silico screening and molecular docking. Molecular dynamics simulations confirmed stable interactions of these drugs with FOXM1. In vitro experiments showed both Pantoprazole and Rabeprazole exhibited strong FOXM1 inhibition at effective concentrations and that showed inhibition of cell proliferation. Rabeprazole showed the inhibitor activity at 10 mu M in BT-20 and MCF-7 cell lines. Pantoprazole exhibited FOXM1 inhibition at 30 mu M and in BT-20 cells and at 70 mu M in MCF-7 cells, respectively. Our current study provides the first evidence that Rabeprazole and Pantoprazole can bind to FOXM1 and inhibit its activity and downstream signaling, including eEF2K and pEF2, in breast cancer cells. These findings indicate that rabeprazole and pantoprazole inhibit FOXM1 and breast cancer cell proliferation, and they can be used for FOXM1-targeted therapy in breast or other cancers driven by FOXM1.
dc.description.sponsorshipScientific and Technological Research Council of Turkiye (TUBIdot;TAK); Canakkale Onsekiz Mart University Research Coordination Unit [FDK-2022-4145]
dc.description.sponsorshipOpen access funding provided by the Scientific and Technological Research Council of Turkiye (TUB & Idot;TAK). Funding for this research was provided by Canakkale Onsekiz Mart University Research Coordination Unit (Project Number: FDK-2022-4145).
dc.identifier.doi10.1007/s12032-024-02427-0
dc.identifier.issn1357-0560
dc.identifier.issn1559-131X
dc.identifier.issue8
dc.identifier.pmid38918225
dc.identifier.scopus2-s2.0-85196835033
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1007/s12032-024-02427-0
dc.identifier.urihttps://hdl.handle.net/20.500.12428/27365
dc.identifier.volume41
dc.identifier.wosWOS:001254161900001
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherHumana Press Inc
dc.relation.ispartofMedical Oncology
dc.relation.publicationcategoryinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WoS_20250125
dc.subjectFOXM1
dc.subjectBreast cancer
dc.subjectTriple-negative breast cancer
dc.subjectDrug repurposing
dc.subjectRabeprazole
dc.subjectPantoprazole
dc.subjectMolecular docking
dc.subjectPharmacophore
dc.subjectTargeted therapy
dc.subjectCell cytotoxicity assay
dc.subjectFOXM1-siRNA transfection
dc.subjectWestern blot
dc.titleA drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells
dc.typeArticle

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