Cucurbitacin B and cisplatin induce the cell death pathways in MB49 mouse bladder cancer model

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dc.contributor.authorKurman, Yener
dc.contributor.authorKiliccioglu, Ilker
dc.contributor.authorDikmen, Asiye U.
dc.contributor.authorEsendagli, Guldal
dc.contributor.authorBilen, Cenk Y.
dc.contributor.authorSozen, Sinan
dc.contributor.authorKonac, Ece
dc.date.accessioned2021-12-01T18:49:14Z
dc.date.available2021-12-01T18:49:14Z
dc.date.issued2020
dc.department[Belirlenecek]en_US
dc.description.abstractCisplatin-based chemotherapy is the standard regimen for bladder cancer patients, but its effectiveness is limited by high toxicity and the development of drug resistance. It has been reported in many studies that Cucurbitacin B has anti-carcinogenic effects by stimulating apoptosis and autophagy. Here we explored the potential role of cucurbitacin B on MB49 bladder syngeneic mouse tumor model. Single and combined doses of cucurbitacin B and cisplatin were applied to MB49 cell line and the cell viability was determined by Water-Soluble Tetrazolium Salt-1 (WST) method. After developing the tumor model, mice were randomly divided into four groups and then cucurbitacin B and cisplatin applied in the specified doses and time. The expression levels of apoptosis (Bcl-2, Bax, Caspase-3, cleaved Caspase-3) and autophagy proteins (Beclin-1 and LC3I, LC3II) were detected by Western Blot. Phospho-protein array analysis was performed to determine the relative levels of phosphorylation of proteins which are associated with the PI3K-Akt signaling pathway. Tumor tissues were analyzed by hematoxylin-eosin staining. In the present study, the results showed that cucurbitacin B inhibited the expression of Bcl-2 and increased the expression of Bax and cleaved Caspase 3. LC3II is markedly up-regulated in cucurbitacin B-treated cells. Cucurbitacin B reduced the phosphorylation of p27, PRAS40, and Raf-1 proteins. CuB + Cis combination synergistically decreased phosphorylation of AKT, ERK1/ERK2, mTOR, BAD levels and increased the level of AMPK alpha. PI3K/AKT/ mTOR pathway might be one of the targets of cucurbitacin B in MB49 bladder cancer mouse model. CuB + Cis combination reduced the tumor growth. Cucurbitacin B has no toxic effects on lung, liver, kidney, heart, and bladder. Indeed, cucurbitacin B can inhibit the tumor proliferation; induce caspase-dependent/-independent apoptosis and autophagy. Our study provided a novel perspective to research the effects of cucurbitacin B on the apoptotic and autophagic pathways in bladder cancer and a new target class for drug development. Impact statement Alternative agents that will increase the effectiveness of cisplatin, which are widely used in the advanced stage and metastatic bladder cancer, are being investigated. In previous studies, Cucurbitacin B (CuB), which is a natural compound from the Cucurbitaceae family has been shown to inhibit the proliferation of tumor cells and create synergistic effects with cisplatin. In this study, we investigated the synergistic effect of CuB with cisplatin for the first time in bladder cancer in vitro and in vivo models. Our findings showed that CuB treatment with cisplatin reduced cell proliferation, and reduced tumor development through activating apoptosis and autophagy via PI3K/AKT/mTOR signaling pathway. Our results showed that CuB may be a new agent that can support conventional treatment in bladder cancer. Our study is important in terms of enlightening new pathways and developing new treatment methods in the treatment of bladder cancer.en_US
dc.description.sponsorshipGazi University Research FundGazi University [01/201828]; Faculty Member Training Program (OYP) of the Council of Higher Education of Turkey (YOK)en_US
dc.description.sponsorshipThis study was conducted with financial support from the Gazi University Research Fund [the project code number 01/201828]; and by the Faculty Member Training Program (OYP) of the Council of Higher Education of Turkey (YOK).en_US
dc.identifier.doi10.1177/1535370220917367
dc.identifier.endpage814en_US
dc.identifier.issn1535-3702
dc.identifier.issn1535-3699
dc.identifier.issue9en_US
dc.identifier.scopus2-s2.0-85083063246en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.startpage805en_US
dc.identifier.urihttps://doi.org/10.1177/1535370220917367
dc.identifier.urihttps://hdl.handle.net/20.500.12684/10688
dc.identifier.volume245en_US
dc.identifier.wosWOS:000524425600001en_US
dc.identifier.wosqualityQ3en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherSage Publications Ltden_US
dc.relation.ispartofExperimental Biology And Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBladder canceren_US
dc.subjectcucurbitacin Ben_US
dc.subjectapoptotic proteinsen_US
dc.subjectautophagic proteinsen_US
dc.subjectsyngeneic mouse modelsen_US
dc.subjectcombination therapyen_US
dc.subjectAntitumor-Activityen_US
dc.subjectUrothelial Canceren_US
dc.subjectAutophagyen_US
dc.subjectApoptosisen_US
dc.subjectRosen_US
dc.subjectCycleen_US
dc.subjectPhosphorylationen_US
dc.subjectProliferationen_US
dc.subjectActivationen_US
dc.subjectJak2/Stat3en_US
dc.titleCucurbitacin B and cisplatin induce the cell death pathways in MB49 mouse bladder cancer modelen_US
dc.typeArticleen_US

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