Therapeutic effect of hydroxychloroquine on colorectal carcinogenesis in experimental murine colitis.
Chronic inflammation in the intestine is a strong risk factor for colitis-associated colorectal cancer (CAC). Hydroxychloroquine (HCQ) is widely used as an anti-inflammatory drug in the treatment of immune-mediated inflammatory disorders and various tumors. However, little is known regarding the effects of HCQ on colitis-associated tumorigenesis. In this study, mice treated with HCQ showed a significant reduction in early-stage colitis following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration, as well as a remarkable inhibition of colonic tumorigenesis and tumor growth at late stages of CAC. Mechanistically, the therapeutic effects of HCQ were attributed to inhibition of inflammatory responses and production of mutagenic reactive oxygen species (ROS) in immune cells and subsequent promotion of apoptosis and cell cycle arrest in tumor cells. Furthermore, we found that HCQ inhibited the production of inflammatory cytokines and ROS in response to toll-like receptor 4 (TLR4) activation in macrophages. Our data presented herein may help guide the clinical use of HCQ as a prevention and treatment strategy for CAC.
Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Junlin
J
Yao
Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Jiansheng
J
Xie
Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Binbin
B
Xie
Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Yiran
Y
Li
Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Liming
L
Jiang
Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Xinbing
X
Sui
Department of Medical Oncology, Hangzhou Xiasha Hospital, Hangzhou, Zhejiang, China.
Xiaoyun
X
Zhou
Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: hongmingpan@gmail.com.
Hongming
H
Pan
Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: hanwd@zju.edu.cn.
Weidong
W
Han
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D063646:Carcinogenesis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D006886:Hydroxychloroquine / Q000627:therapeutic use*; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D017382:Reactive Oxygen Species; D006886:Hydroxychloroquine
Colitis-associated colorectal cancer; Hydroxychloroquine; Macrophages; Reactive oxygen species; Toll-like receptor 4