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Sci Rep. 2016 Apr 19;6:24675. doi: 10.1038/srep24675.

Curcumin mediates oxaliplatin-acquired resistance reversion in colorectal cancer cell lines through modulation of CXC-Chemokine/NF-κB signalling pathway.

Author information

1
Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), Can Ruti Campus, Ctra. Can Ruti- Camí de les escoles s/n, 08916, Badalona, Spain.
2
Resistance, chemotherapy and predictive biomarkers group. ProCURE (Program against cancer resistance). Catalan Institute of Oncology. Edifici IGTP, Carretera de Can Ruti, Camí de les escoles, s/n, Campus Can Ruti, 08916 Badalona, Spain.
3
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199. 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
4
Genomics and Bioinformatics Unit, Institute for Predictive and Personalized Medicine of Cancer (IMPPC), Can Ruti Campus, Ctra. Can Ruti- Camí de les escoles s/n, 08916, Badalona, Spain.
5
Dept Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
6
Medical Oncology Service, Catalan Institute of Oncology (ICO) University Hospital Germans TriasiPujol, Ctra. Can Ruti- Camí de les escoles s/n, 08916, Badalona, Spain.
7
Oncology Unit, Hospital CIMA Sanitas, Barcelona, Catalonia, Spain.

Abstract

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.

PMID:
27091625
PMCID:
PMC4835769
DOI:
10.1038/srep24675
[Indexed for MEDLINE]
Free PMC Article

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