Curcumin mediates oxaliplatin-acquired resistance reversion in colorectal cancer cell lines through modulation of CXC-Chemokine/NF-κB signalling pathway
Ruiz de Porras, Vicenç (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Bystrup, Sara (Institut Germans Trias i Pujol)
Martínez Cardús, Anna (Institut d'Investigació Biomèdica de Bellvitge)
Pluvinet, Raquel (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Sumoy, Lauro (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Howells, Lynne (University of Leicester. Departament of Cancer Studies)
James, Mark I. (University of Leicester. Departament of Cancer Studies)
Iwuji, Chinenye (University of Leicester. Departament of Cancer Studies)
Manzano, José Luis (Institut Germans Trias i Pujol)
Layos, Laura (Institut Germans Trias i Pujol)
Bugés, Cristina (Institut Germans Trias i Pujol)
Abad, Albert (Hospital Cima Sanitas (Barcelona))
Martínez Balibrea, Eva (Institut Germans Trias i Pujol)

Data:	2016
Resum:	Resistance to oxaliplatin (OXA) is a complex process affecting the outcomes of metastatic colorectal cancer (CRC) patients treated with this drug. De-regulation of the NF-κB signalling pathway has been proposed as an important mechanism involved in this phenomenon. Here, we show that NF-κB was hyperactivated in in vitro models of OXA-acquired resistance but was attenuated by the addition of Curcumin, a non-toxic NF-κB inhibitor. The concomitant combination of Curcumin + OXA was more effective and synergistic in cell lines with acquired resistance to OXA, leading to the reversion of their resistant phenotype, through the inhibition of the NF-κB signalling cascade. Transcriptomic profiling revealed the up-regulation of three NF-κB-regulated CXC-chemokines, CXCL8, CXCL1 and CXCL2, in the resistant cells that were more efficiently down-regulated after OXA + Curcumin treatment as compared to the sensitive cells. Moreover, CXCL8 and CXCL1 gene silencing made resistant cells more sensitive to OXA through the inhibition of the Akt/NF-κB pathway. High expression of CXCL1 in FFPE samples from explant cultures of CRC patients-derived liver metastases was associated with response to OXA + Curcumin. In conclusion, we suggest that combination of OXA + Curcumin could be an effective treatment, for which CXCL1 could be used as a predictive marker, in CRC patients.
Ajuts:	Instituto de Salud Carlos III PI1202228
Nota:	This study was funded by the ISCIII grant, project n° PI1202228 and Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya. SGR-PREDIVHICO. This work was done under the framework of the doctorate in Medicine from the Universitat Autònoma de Barcelona. We thank Dr. Lucía Sanjurjo (Innate Immunity Group, IGTP, Badalona, Spain) for her technical assistance and support and Dr. Verónica Guirao (Biobank research support unit, IGTP, Badalona, Spain) for her comments and editorial assistance.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Curcumina ; Oxaliplatí ; Còlon ; Càncer ; Recte ; CRC ; Curcumin
Publicat a:	Scientific reports, Vol. 6 (April 2016) , ISSN 2045-2322

DOI: 10.1038/srep24675
PMID: 27091625

17 p, 2.9 MB

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