Curcumin mediates oxaliplatin-acquired resistance reversion in colorectal cancer cell lines through modulation of CXC-Chemokine/NF-κB signalling pathway.
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.
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.
Vicenç
V
Ruiz de Porras
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.
Sara
S
Bystrup
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199. 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
Anna
A
Martínez-Cardús
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.
Raquel
R
Pluvinet
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.
Lauro
L
Sumoy
Dept Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
Lynne
L
Howells
Dept Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
Mark I
MI
James
Dept Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
Chinenye
C
Iwuji
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.|Medical Oncology Service, Catalan Institute of Oncology (ICO) University Hospital Germans TriasiPujol, 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.
José Luis
JL
Manzano
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.|Medical Oncology Service, Catalan Institute of Oncology (ICO) University Hospital Germans TriasiPujol, 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.
Laura
L
Layos
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.|Medical Oncology Service, Catalan Institute of Oncology (ICO) University Hospital Germans TriasiPujol, 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.
Cristina
C
Bugés
Oncology Unit, Hospital CIMA Sanitas, Barcelona, Catalonia, Spain.
Albert
A
Abad
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.
Eva
E
Martínez-Balibrea
D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019743:Chemokines, CXC; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003474:Curcumin