Show simple item record

dc.contributor.authorMaliandi, Maria V
dc.contributor.authorMato-Berciano, Ana
dc.contributor.authorSobrevals, Luciano
dc.contributor.authorRoué, Gaël
dc.contributor.authorJosé, Anabel
dc.contributor.authorFillat, Cristina
dc.date.accessioned2015-09-01T18:23:12Z
dc.date.available2015-09-01T18:23:12Z
dc.date.issued2015-07-31
dc.identifier.citationMolecular Cancer. 2015 Jul 31;14(1):146
dc.identifier.urihttp://dx.doi.org/10.1186/s12943-015-0413-2
dc.identifier.urihttp://hdl.handle.net/10724/32009
dc.description.abstractAbstract Background Combined treatment of oncolytic adenoviruses with chemotherapeutic agents is foreseen as a therapeutic option for cancer. Here we have investigated the potential to use gemcitabine in combination with the oncolytic adenovirus AduPARE1A to treat pancreatic cancer and evaluate the underlying mechanism. Methods We treated pancreatic cancer cell lines BxPC-3 and PANC-1 with AduPARE1A and gemcitabine individually or in combination and analyzed cell viability, combination index, apoptosis and viral production. We also investigated the effects of the combination on tumor growth and mice survival in two xenograft models. Furthermore, we analyzed uPAR promoter activity from different uPAR-controlled adenovirus and studied NF-κB mediated effects. Results Synergistic cell killing from the combination AduPARE1A/Gemcitabine was observed in BxPC-3 and PANC-1 cells. Moreover, the combination treatment produced therapeutic benefits over either individual modality in two mouse models bearing orthotopic tumors, showing reduced tumor progression and significant prolonged mouse survival. Mechanistic studies showed that the synergistic cell death was not due to an increase in viral replication but occurred through an enhancement of apoptotic cell death. Gemcitabine stimulation increased the transcription of uPAR-controlled transgenes through the induction of NF-κB acting on the uPAR promoter. Interestingly, NF-κB gemcitabine-mediated induction of AduPAR adenoviruses interfered with the activation of NF-κB regulated genes, probably as a result of an intracellular competition for NF-κB DNA binding. Consequently, AduPARE1A infection sensitized cells to gemcitabine-induced apoptosis in the combined treatment. Conclusions These data highlights the potential of the combination as a treatment modality for pancreatic cancer patients.
dc.titleAduPARE1A and gemcitabine combined treatment trigger synergistic antitumor effects in pancreatic cancer through NF-κB mediated uPAR activation
dc.typeJournal Article
dc.date.updated2015-07-31T03:39:30Z
dc.language.rfc3066en
dc.rights.holderMaliandi et al.


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record