Induction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives

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dc.contributor.authorYilmaz, Sinem
dc.contributor.authorTok, F.
dc.contributor.authorAtalay-Sahar, Esra
dc.contributor.authorKoçyi?it-Kaymakçio?lu, Bedi?A
dc.contributor.authorBallarkırmızıbayrak, Petek
dc.date.accessioned2026-01-24T12:20:50Z
dc.date.available2026-01-24T12:20:50Z
dc.date.issued2022
dc.departmentAlanya Alaaddin Keykubat Üniversitesi
dc.description.abstractBackground: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of Endoplasmic Reticulum (ER) stress and subsequent activation of the Unfolded Protein Response (UPR) has been proposed as a potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis. Objective: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives. Methods: Cell proliferation assays were performed on HeLa, Capan-1, MCF-7, HCC-1937, and MRC-5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis. Results: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of proapoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and-7. The flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells). Conclusion: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways. © 2022 Bentham Science Publishers.
dc.description.sponsorshipTürkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK, (215S112)
dc.identifier.doi10.2174/1871520621666210528153949
dc.identifier.endpage1768
dc.identifier.issn1871-5206
dc.identifier.issue9
dc.identifier.pmid34053426
dc.identifier.scopus2-s2.0-85127979510
dc.identifier.scopusqualityQ3
dc.identifier.startpage1761
dc.identifier.urihttps://doi.org/10.2174/1871520621666210528153949
dc.identifier.urihttps://hdl.handle.net/20.500.12868/4610
dc.identifier.volume22
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherBentham Science Publishers
dc.relation.ispartofAnti-Cancer Agents in Medicinal Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_Scopus_20260121
dc.subjectapoptosis
dc.subjectcarbohydrazide derivatives
dc.subjectcell death
dc.subjectCHOP
dc.subjectnecrosis
dc.subjectUPR
dc.subjecturea
dc.titleInduction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives
dc.typeArticle

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