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Theranostics 2020; 10(15):6743-6757. doi:10.7150/thno.43938 This issue Cite

Research Paper

An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer

Yue Kuai^1#, Hao Liu^1,2#, Dongyu Liu^3#, Yunlong Liu¹, Ye Sun¹, Jiansheng Xie^1,2, Jiachun Sun⁴, Yong Fang¹, Hongming Pan^1,2✉, Weidong Han^1,2✉

1. Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
2. Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
3. Department of Orthopedics, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
4. The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology.
#These authors contributed equally to this work.

✉ Corresponding authors: Weidong Han. Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, Zhejiang, China, 310016. Phone: +86-571-86006926, E-mail: hanwdedu.cn; Hongming Pan. Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, Zhejiang, China, 310016. Phone: +86-571-86006926; E-mail: panhongmingedu.cn. More

Abstract

Long-term inflammatory stimulation is considered one of the most important causes of colorectal cancer. Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, can inhibit a variety of inflammatory responses. However, the systemic toxicity of DPI limits its clinical application. Whether DPI can inhibit colitis-associated colorectal cancer (CAC) at ultralow concentrations remains unknown.

Methods: CAC was induced by azoxymethane (AOM) injection followed by treatment with dextran sulfate sodium (DSS), and DPI was intraperitoneally injected (i.p.) in the first cycle for 21 days. Colon tissue was collected and analyzed by western blotting. Immune cell infiltration and macrophage polarization were examined by immunohistochemistry, immunofluorescence, or real-time polymerase-chain reaction (PCR). Reactive oxygen species (ROS) production was measured by flow cytometry.

Results: Ultralow dose DPI significantly ameliorated the DSS-induced colitis and attenuated the colon tumorigenesis in the mouse model of AOM/ DSS-induced CAC. Mechanistically, an ultralow dose of DPI inhibited the production of pro-inflammatory cytokines, (tumor necrosis factor (TNF)-α and interleukin (IL)-6), reduced the macrophage infiltration and classical polarization, and induced the ROS generation. These effects were found to be related to the inhibition of the phosphorylation of signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF -κB).

Conclusion: The present study revealed that an ultralow dose of DPI, with no significant systemic toxicity involved, may be an effective way to prevent the occurrence and development of CAC.

Keywords: colitis-associated colorectal cancer, diphenyleneiodonium, NADPH oxidase inhibitor, macrophage, polarization

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