Investigating EGFR-VEGF-mediated apoptotic effect of cucurbitacin D and I combination with sorafenib via Ras/Raf/MEK/ERK and PI3K/Akt signaling pathways

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dc.contributor.authorUremis, Nuray
dc.contributor.authorTurkoz, Yusuf
dc.contributor.authorUremis, Muhammed Mehdi
dc.contributor.authorCigremis, Yilmaz
dc.contributor.authorSalva, Emine
dc.date.accessioned2024-08-04T20:54:48Z
dc.date.available2024-08-04T20:54:48Z
dc.date.issued2024
dc.departmentİnönü Üniversitesien_US
dc.description.abstractSorafenib, which is a type of systemic multi-kinase inhibitor drug, is used for first-line therapy in treating hepatocellular carcinoma (HCC). In this study, the anticarcinogenic effects of sorafenib-cucurbitacin D and sorafenib-cucurbitacin I combination on HepG2 cell line were investigated. Cell inhibition, migration, apoptosis, cell cycle distribution, mitochondrial membrane potential (Delta psi m), colony formation, and wound healing were investigated by applying cucurbitacin D and I alone or in combination with sorafenib to HepG2 cells. In addition, in order to reveal how cucurbitacins affect the signal pathways known to affect sorafenib; proteins and genes involved in VEGF, EGFR, MMP-2, caspase cascade, PI3K/AKT/mTOR, Raf/MEK/ERK signaling pathways were assessed by western blot and qRT-PCR. It has been shown that cucurbitacin D and I have an antiproliferative effect at low concentrations and show a synergistic effect when combined with sorafenib. Combined administrations induced apoptosis by increasing caspase-9, Bax activity and inhibiting Bcl-xL activation, blocking the cell cycle in G2/M phase and causing loss of Delta psi m. The combinations also suppressed MMP-2 and VEGF, reduced cell migration. The combined cucurbitacin-sorafenib applications inhibited the expression of proteins and genes involved in EGFR and PI3K/AKT/mTOR, Raf/MEK/ERK signaling pathways. Due to showing the synergetic effect of cucurbitacins with sorafenib and their targeting of similar signaling pathways reveal that their combination may increase the efficacy of sorafenib by suppressing angiogenic, metastatic and proliferative activity in HCC.en_US
dc.description.sponsorshipThe authors express their deep gratitude to Bayer Health Care Pharmaceuticals Inc. for offering the pure sorafenib material for the contemplated research.en_US
dc.description.sponsorshipThe authors express their deep gratitude to Bayer Health Care Pharmaceuticals Inc. for offering the pure sorafenib material for the contemplated research.en_US
dc.identifier.doi10.1007/s00210-023-02811-z
dc.identifier.endpage3247en_US
dc.identifier.issn0028-1298
dc.identifier.issn1432-1912
dc.identifier.issue5en_US
dc.identifier.pmid37917368en_US
dc.identifier.scopus2-s2.0-85175815769en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.startpage3247en_US
dc.identifier.urihttps://doi.org/10.1007/s00210-023-02811-z
dc.identifier.urihttps://hdl.handle.net/11616/101654
dc.identifier.volume397en_US
dc.identifier.wosWOS:001093223800001en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherSpringeren_US
dc.relation.ispartofNaunyn-Schmiedebergs Archives of Pharmacologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectCucurbitacinen_US
dc.subjectSorafeniben_US
dc.subjectEGFR-VEGFen_US
dc.subjectPI3K/AKTen_US
dc.subjectRas/Raf/MEK/ERKen_US
dc.subjectCaspaseen_US
dc.titleInvestigating EGFR-VEGF-mediated apoptotic effect of cucurbitacin D and I combination with sorafenib via Ras/Raf/MEK/ERK and PI3K/Akt signaling pathwaysen_US
dc.typeArticleen_US

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