Yan Y, Lin HW, Zhuang ZN, Li M, Guo S. Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer. World J Gastrointest Oncol 2020; 12(8): 877-892 [PMID: 32879665 DOI: 10.4251/wjgo.v12.i8.877]
Corresponding Author of This Article
Sen Guo, PhD, Adjunct Professor, Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Street, Jinan 250012, Shandong Province, China. guosen4321@163.com
Research Domain of This Article
Oncology
Article-Type of This Article
Basic Study
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Yan Y, Lin HW, Zhuang ZN, Li M, Guo S. Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer. World J Gastrointest Oncol 2020; 12(8): 877-892 [PMID: 32879665 DOI: 10.4251/wjgo.v12.i8.877]
World J Gastrointest Oncol. Aug 15, 2020; 12(8): 877-892 Published online Aug 15, 2020. doi: 10.4251/wjgo.v12.i8.877
Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer
Yan Yan, Hong-Wei Lin, Zhuo-Nan Zhuang, Ming Li, Sen Guo
Yan Yan, Department of Operating Room, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
Hong-Wei Lin, Zhuo-Nan Zhuang, Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University, Beijing 102200, China
Ming Li, Department of General Surgery, Zouping Traditional Chinese Medicine Hospital, Zhouping 256200, Shandong Province, China
Sen Guo, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Yan Y, Lin HW, and Zhuang ZN contributed equally to this work and should be regarded as co-first authors; Yan Y and Guo S were major contributors in writing the manuscript and analyzing the data; Lin HW and Zhuang ZN made substantial contributions to the study design; Li M was a major contributor in performing the animal experiments; and all authors read and approved the final manuscript.
Supported byBeijing Tsinghua Changgung Hospital Fund, No. 12015C1042; Bethune-Excellent Surgery Fund, No. HZB-20181119-13; and Chen Xiaoping Science and Technology Development Fund, No. CXPJH11800004-021.
Institutional animal care and use committee statement: The study was reviewed and approved by the Animal Ethics Committee of Qilu Hospital of Shandong University.
Conflict-of-interest statement: All the authors have nothing to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Sen Guo, PhD, Adjunct Professor, Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Street, Jinan 250012, Shandong Province, China. guosen4321@163.com
Received: May 12, 2020 Peer-review started: May 12, 2020 First decision: June 15, 2020 Revised: June 20, 2020 Accepted: July 26, 2020 Article in press: July 26, 2020 Published online: August 15, 2020 Processing time: 91 Days and 22.3 Hours
ARTICLE HIGHLIGHTS
Research background
The systemic toxicity and drug resistance of tumor cells are still two major problems in cancer chemotherapy. The chemotherapeutic drug 5-fluorouracil (5-FU) can inhibit the synthesis of adenylate synthetase and interfere with the synthesis of DNA in tumor cells. The effect of 5-FU is not ideal due to the chemoresistance in colon carcinoma patients treated with 5-FU.
Research motivation
Interleukin (IL)-1 and nuclear factor kappa-B (NF-κB) show a cyclic relationship, which leads to persistent activation of NF-κB in tumor cells. In Kras and p53 gene mutant mice, we found that the activity of NF-κB was downregulated by inhibiting the IL-1 receptor, which could effectively slow tumor growth.
Research objectives
The aim of this study was to determine whether treatment with 5-FU combined with IL-1 receptor antagonist can increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells. The results obtained provide a theoretical basis for clinical adjuvant chemotherapy.
Research methods
The expression of phosphorylated P65 in the COLO205, SW620, and HCT116 cell lines was significantly higher than that in the NCM460 cell line, as shown by Western blot assays. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1α feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting colon tumor cell growth.
Research results
IL-1RA combined with 5-FU showed stronger inhibition of the proliferation of the SW620 and HCT116 cell lines than 5-FU treatment. IL-1RA combined with 5-FU treatment had a greater effect in extending the survival time of the tumor-bearing nude mice than 5-FU single therapy.
Research conclusions
IL-1 receptor antagonist combined with 5-FU has a stronger inhibitory effect on the proliferation of colon cancer cells than 5-FU alone due to the blockade of IL-1.
Research perspectives
These results could provide an adjuvant chemotherapy strategy for the clinic and provide a theoretical basis for neoadjuvant chemotherapy.
