A Novel 6,8,9-Trisubstituted Purine Analogue Drives Breast Cancer Luminal A Subtype MCF-7 to Apoptosis and Senescence through Hsp70 Inhibition

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dc.authoridTUTAR, Yusuf/0000-0003-2613-9644
dc.authoridYenilmez Tunoglu, Ezgi Nurdan/0000-0001-7866-7890
dc.authoridKul, Pinar/0000-0003-3639-0496
dc.contributor.authorKul, Pinar
dc.contributor.authorTuncbilek, Meral
dc.contributor.authorErgul, Mustafa
dc.contributor.authorTunoglu, Ezgi Nurdan Yenilmez
dc.contributor.authorTutar, Yusuf
dc.date.accessioned2024-10-26T18:08:10Z
dc.date.available2024-10-26T18:08:10Z
dc.date.issued2023
dc.departmentSivas Cumhuriyet Üniversitesi
dc.description.abstractBackground: Cancer cells restrain apoptotic and senescence pathways through intracellular heat shock protein 70 (Hsp 70). These cells aid stimulus-independent growth, and their higher metabolism rate requires Hsps. Hsps compensate abnormally increased substrate protein folding rate of cancer cells. Objective: Misfolding of substrate proteins especially signaling substrate proteins, may not function properly. Therefore, Hsp70 folds these substrate proteins into their native-fully functional states, and this mode of action helps cancer cell survival. Methods: Targeting Hsps is promising cancer therapy, and in this study, 6,8,9-trisubstituted purine derivatives were designed and synthesized to inhibit Hsp70 and drive cancer cells to apoptosis. Further, oncogenic stimuli through inhibitors can induce an irreversible senescent state and senescence is a barrier to transformation. Results: Hsp70 helps cancer cells to bypass the cellular senescence program, however, binding of N-6-(4-isopropylaniline) analogue (7) depletes Hsp70 function as evidenced by aggregation assay and Hsp70 depletion induces senescence pathway. Conclusion: The purine-based inhibitor-compound 7 effectively inhibits MCF-7 cell line. Moreover, the therapeutic potential with regard to the senescence-associated secretory phenotype has complementary action. Dual action of the inhibitor not only drives the cells to apoptosis but also force the cells to be in the senescence state and provides promising results specially for luminal A type breast cancer therapy.
dc.identifier.doi10.2174/1871520622666220905122346
dc.identifier.endpage598
dc.identifier.issn1871-5206
dc.identifier.issn1875-5992
dc.identifier.issue5
dc.identifier.pmid36065916
dc.identifier.scopus2-s2.0-85147569245
dc.identifier.scopusqualityQ3
dc.identifier.startpage585
dc.identifier.urihttps://doi.org/10.2174/1871520622666220905122346
dc.identifier.urihttps://hdl.handle.net/20.500.12418/29849
dc.identifier.volume23
dc.identifier.wosWOS:000959513700008
dc.identifier.wosqualityQ3
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherBentham Science Publ Ltd
dc.relation.ispartofAnti-Cancer Agents in Medicinal Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectPurine analogues
dc.subjectcytotoxic activity
dc.subjectdrug design
dc.subjectapoptosis
dc.subjectsenescence
dc.subjectHsp70 inhibition
dc.titleA Novel 6,8,9-Trisubstituted Purine Analogue Drives Breast Cancer Luminal A Subtype MCF-7 to Apoptosis and Senescence through Hsp70 Inhibition
dc.typeArticle

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