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- Title
Targeting of MyD88 Homodimerization by Novel Synthetic Inhibitor TJ-M2010-5 in Preventing Colitis-Associated Colorectal Cancer.
- Authors
Lin Xie; Feng-Chao Jiang; Li-Min Zhang; Wen-Tao He; Jian-Hua Liu; Ming-Qiang Li; Xue Zhang; Shuai Xing; Hui Guo; Ping Zhou; Xie, Lin; Jiang, Feng-Chao; Zhang, Li-Min; He, Wen-Tao; Liu, Jian-Hua; Li, Ming-Qiang; Zhang, Xue; Xing, Shuai; Guo, Hui; Zhou, Ping
- Abstract
<bold>Background: </bold>The TLR/MyD88 signaling pathway is an important driver of inflammation and cancer and is a possible target for antitumor therapy.<bold>Methods: </bold>We generated a MyD88 inhibitor (TJ-M2010-5), which was designed to bind to the TIR domain of MyD88 to interfere with its homodimerization, and the TLR/MyD88 signal pathway. We utilized a mouse model of azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated cancer (CAC) in combination with TJ-M2010-5 administration to investigate the anti-inflammation-related cancer effect of MyD88 inhibitor in vivo. Data were analyzed with one-way and repeated measures analysis of variance. Differences in survival between groups were compared using the log rank test. All statistical tests were two-sided.<bold>Results: </bold>TJ-M2010-5 inhibited MyD88 homodimerization in transfected HEK293 cells in a concentration-dependent manner and suppressed MyD88 signaling in LPS-responsive RAW 264.7 cells in vitro. In a 10-week CAC mouse model (n = 30 per group), TJ-M2010-5 treatment statistically significantly reduced AOM/DSS-induced colitis and completely prevented CAC development with less related body mass loss, resulted in 0% mortality of treated mice (compared with 53% mortality of control mice), decreased cell proliferation, and increased apoptosis in colon tissue. TJ-M2010-5 treatment also inhibited production of inflammatory cytokines and chemokines (TNF-α, IL-6,G-CSF, MIP-1β, TGF-β1, IL-11, IL-17A, IL-22 and IL-23) and infiltration of immune cells (macrophages, dendritic cells, neutropihls and CD(+)4 T cells) in colon tissues of mice.<bold>Conclusions: </bold>Our findings suggest that TLR/MyD88 signaling may be a therapeutic target for CAC intervention and MyD88 inhibitors may be a promising therapeutic modality for treating patients with colitis or CAC.
- Subjects
COLON diseases; COLON cancer; COLITIS; DIMERIZATION; CHEMICAL inhibitors; TUMOR prevention; COLON tumor prevention; ANIMALS; ANTINEOPLASTIC agents; BIOCHEMISTRY; BIOLOGICAL models; CARRIER proteins; CELLULAR signal transduction; CHEMOKINES; DRUG therapy; COLON tumors; CYTOKINES; ENZYME-linked immunosorbent assay; FLOW cytometry; GENETIC techniques; HETEROCYCLIC compounds; IMMUNOHISTOCHEMISTRY; PHENOMENOLOGY; MICE; POLYMERASE chain reaction; RECTUM tumors; THIAZOLES; DISEASE complications; PHARMACODYNAMICS
- Publication
JNCI: Journal of the National Cancer Institute, 2016, Vol 108, Issue 4, p1
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djv364