CXCL1型
趋化因子受体
姜黄素
白细胞介素8
癌症研究
奥沙利铂
CXCL2型
细胞培养
基因沉默
趋化因子
结直肠癌
基因敲除
药理学
医学
化学
生物
细胞因子
炎症
免疫学
趋化因子受体
癌症
内科学
生物化学
基因
遗传学
作者
Vicenç Ruiz de Porras,Sara Bystrup,Anna Martínez-Cardús,Raquel Pluvinet,Lauro Sumoy,Lynne M. Howells,Mark James,Chinenye Iwuji,Jose Luis Manzano,Laura Layos,Cristina Buges,Albert Abad,Eva Martinez-Balibrea
摘要
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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