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

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.

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis

“…Emerging evidence suggests that several conventional cancer chemotherapeutic agents that activate NF-κB/p65 lead to unfavorable clinical outcome [27,32,33], and the DNA-binding ability of NF-κB/ p65 has been proposed as a major mechanism contributing to chemoresistance in CRC [9,22,34]. The naturally occurring compound thymoquinone could abrogate oxaliplatin-induced activation of NF-κB/p65 and enhance sensitivity to oxaliplatin in pancreatic cancer [32].…”

Antibacterial Action of Curcumin against Staphylococcus aureus: A Brief Review

“…More studies are needed to evaluate the mechanism of curcumin synergism based on the different classes of antibiotics. In addition to antibacterial action, curcumin also reverses the drug resistance when used in combination with other anticancer agents such as cisplatin, 5-fluorouracil, oxaliplatin, and doxorubicin in multiple types of cancer cells including breast [68], colon [69], head and neck [70], and ovary [71]. The curcumin may have acted on the target or pathway related to the development of drug resistance, hence restoring the killing effect of the drugs [72, 73].…”

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

“…3 In fact, the exact underlying molecular mechanism responsible for L-OHP resistance remains elusive up to now. Resistance to L-OHP is a complex process and several signaling pathways, such as the nuclear factor-kappa B (NF-κB) pathway, 4 the extracellular signal-regulated kinase (ERK)/Extracellular signal-regulated kinase (MEK) pathway, 5 and the protein kinase B (AKT/PKB) pathway, 6 have been involved in this phenomenon. Accumulating evidences demonstrate that activation of the AKT signaling pathway always leads to resistance to L-OHP induced apoptosis.…”