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Cancer Chemother Pharmacol. 2018 Jun;81(6):1111-1119. doi: 10.1007/s00280-018-3584-x. Epub 2018 Apr 24.

IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1).

Du J1,2, He Y3, Li P1,2, Wu W1,2, Chen Y1,2, Ruan H4,5,6.

Author information

1
Department of Gastroenterology, Zhejiang Provincial People's Hospital, 158# Shangtang Rd, Hangzhou, Zhejiang Province, 310014, People's Republic of China.
2
People's Hospital of Hangzhou Medical College, Hangzhou, 310014, People's Republic of China.
3
Department of Laboratory Animal Science, Nanchang University, Nanchang, 330006, People's Republic of China.
4
Department of Gastroenterology, Zhejiang Provincial People's Hospital, 158# Shangtang Rd, Hangzhou, Zhejiang Province, 310014, People's Republic of China. hongjunruan@126.com.
5
People's Hospital of Hangzhou Medical College, Hangzhou, 310014, People's Republic of China. hongjunruan@126.com.
6
Department of Gastroenterology, Central Hospital of Haining, Haining, 314499, People's Republic of China. hongjunruan@126.com.

Abstract

Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

KEYWORDS:

CRC; Dox resistance; IL-8; MDR1; P65

PMID:
29693201
DOI:
10.1007/s00280-018-3584-x
[Indexed for MEDLINE]

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