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
Authors: Ye Sun
Dongyu Liu
Hongming Pan
Jiachun Sun
Yunlong Liu
Hao Liu
Yong Fang
Jiansheng Xie
Weidong Han
Yue Kuai
Journal: Theranostics (2020)
Discipline: CLINICAL MEDICINE
Keywords: NADPH oxidase inhibitor; colitis-associated colorectal cancer; diphenyleneiodonium; macrophage; polarization.
Affiliations: Department of Medical Oncology, 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., Department of Orthopedics, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology.

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. 

Retracted: No

PubPeer comments:
 Figure 4F. It is surprising that the two bar graphs shown in red boxes are identical, yet should be different as reflect the effect of various treatments on the mRNA expression of **different genes**. ![file] , 
 #1 ![file] Dear Hypocrella Schizostachyi, Thanks for your letter to point out the mistake on our paper u2018An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal canceru2019 [2020; 10(15): 6743- 6757. doi: 10.7150 thno.43938] Here we clarify the error we have made with attached pictures. Pic.1 is the original Fig. 4F in which the results of TNF-u03b1 and COX2 in BMDM group mistakenly used the same image. We apologized for the negligence and carelessness in the drawing process. We will contact the editorial department to correct this problem.![file] Pic 2 shows the corrected results. ![file] We regret that we didnu2019t find out the mistakes before our submission.We accidentally made a mistake in merging the figures. The correct figure and original data are attached. We confirm that the correction will not affect the results and scientific conclusions of our article, and will contact the editorial department to correct this problem. We are deeply sorry for this. Yours sincerely, Weidong Han , 
 Dear Dr. Han, thanks for your reply. However, the original PCR data you provided are not the raw data. Could you please show the Ct values to rule out the concern? , 
 Dear Hypocrella Schizostachyiuff0c According to your requirements, the figure is CP value, we hope it could meet your requirements . We will be more careful in the process of picture merging in the future. Thank you for your reading. Yours sincerely, Weidong Han ![file] ,