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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.

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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.
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.
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199. 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
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.
Dept Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
Medical Oncology Service, Catalan Institute of Oncology (ICO) University Hospital Germans TriasiPujol, Ctra. Can Ruti- Camí de les escoles s/n, 08916, Badalona, Spain.
Oncology Unit, Hospital CIMA Sanitas, Barcelona, Catalonia, Spain.


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.

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