RGD Reference Report - Targeting of MyD88 Homodimerization by Novel Synthetic Inhibitor TJ-M2010-5 in Preventing Colitis-Associated Colorectal Cancer. - Rat Genome Database

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Targeting of MyD88 Homodimerization by Novel Synthetic Inhibitor TJ-M2010-5 in Preventing Colitis-Associated Colorectal Cancer.

Authors: 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 
Citation: Xie L, etal., J Natl Cancer Inst. 2015 Dec 28;108(4). pii: djv364. doi: 10.1093/jnci/djv364. Print 2016 Apr.
RGD ID: 150520168
Pubmed: PMID:26712311   (View Abstract at PubMed)
DOI: DOI:10.1093/jnci/djv364   (Journal Full-text)


BACKGROUND: The TLR/MyD88 signaling pathway is an important driver of inflammation and cancer and is a possible target for antitumor therapy.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MYD88HumanColitis-Associated Neoplasms amelioratesISOMyd88 (Mus musculus) RGD 
Myd88RatColitis-Associated Neoplasms amelioratesISOMyd88 (Mus musculus) RGD 
Myd88MouseColitis-Associated Neoplasms amelioratesIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Myd88  (MYD88, innate immune signal transduction adaptor)

Genes (Mus musculus)
Myd88  (myeloid differentiation primary response gene 88)

Genes (Homo sapiens)
MYD88  (MYD88 innate immune signal transduction adaptor)


Additional Information