Publication:
Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells.

dc.contributor.authorJiménez-Guerrero, Rocío
dc.contributor.authorGasca, Jessica
dc.contributor.authorFlores, M Luz
dc.contributor.authorPérez-Valderrama, Begoña
dc.contributor.authorTejera-Parrado, Cristina
dc.contributor.authorMedina, Rafael
dc.contributor.authorTortolero, María
dc.contributor.authorRomero, Francisco
dc.contributor.authorJapón, Miguel A
dc.contributor.authorSáez, Carmen
dc.date.accessioned2023-01-25T10:26:31Z
dc.date.available2023-01-25T10:26:31Z
dc.date.issued2018-12-05
dc.description.abstractPaclitaxel is a treatment option for advanced or metastatic bladder cancer after the failure of first-line cisplatin and gemcitabine, although resistance limits its clinical benefits. Mcl-1 is an anti-apoptotic protein that promotes resistance to paclitaxel in different tumors. Obatoclax, a BH3 mimetic of the Bcl-2 family of proteins, antagonizes Mcl-1 and hence may reverse paclitaxel resistance in Mcl-1-overexpressing tumors. In this study, paclitaxel-sensitive 5637 and -resistant HT1197 bladder cancer cells were treated with paclitaxel, obatoclax, or combinations of both. Apoptosis, cell cycle, and autophagy were measured by Western blot, flow cytometry, and fluorescence microscopy. Moreover, Mcl-1 expression was analyzed by immunohistochemistry in bladder carcinoma tissues. Our results confirmed that paclitaxel alone induced Mcl-1 downregulation and apoptosis in 5637, but not in HT1197 cells; however, combinations of obatoclax and paclitaxel sensitized HT1197 cells to the treatment. In obatoclax-treated 5637 and obatoclax + paclitaxel-treated HT1197 cells, the blockade of the autophagic flux correlated with apoptosis and was associated with caspase-dependent cleavage of beclin-1. Obatoclax alone delayed the cell cycle in 5637, but not in HT1197 cells, whereas combinations of both retarded the cell cycle and reduced mitotic slippage. In conclusion, obatoclax sensitizes HT1197 cells to paclitaxel-induced apoptosis through the blockade of the autophagic flux and effects on the cell cycle. Furthermore, Mcl-1 is overexpressed in many invasive bladder carcinomas, and it is related to tumor progression, so Mcl-1 expression may be of predictive value in bladder cancer.
dc.identifier.doi10.3390/cancers10120490
dc.identifier.issn2072-6694
dc.identifier.pmcPMC6316685
dc.identifier.pmid30563080
dc.identifier.pubmedURLhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316685/pdf
dc.identifier.unpaywallURLhttps://www.mdpi.com/2072-6694/10/12/490/pdf?version=1543998234
dc.identifier.urihttp://hdl.handle.net/10668/13326
dc.issue.number12
dc.journal.titleCancers
dc.journal.titleabbreviationCancers (Basel)
dc.language.isoen
dc.organizationInstituto de Biomedicina de Sevilla-IBIS
dc.organizationHospital Universitario Virgen del Rocío
dc.organizationHospital Universitario Virgen del Rocío
dc.organizationHospital Universitario Virgen del Rocío
dc.organizationHospital Universitario Virgen del Rocío
dc.pubmedtypeJournal Article
dc.rightsAttribution 4.0 International
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectapoptosis
dc.subjectautophagy
dc.subjectbladder cancer
dc.subjectobatoclax
dc.subjectpaclitaxel
dc.titleObatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells.
dc.typeresearch article
dc.type.hasVersionVoR
dc.volume.number10
dspace.entity.typePublication

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