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

• Published in: JNCI : Journal of the National Cancer Institute Vol. 108; no. 4; p. djv364
• Main 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
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Animals; Antineoplastic Agents - pharmacology; Chemokines - antagonists & inhibitors; Colitis - complications; Colorectal Neoplasms - etiology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - prevention & control; Cytokines - antagonists & inhibitors; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy - methods; Myeloid Differentiation Factor 88 - antagonists & inhibitors; Myeloid Differentiation Factor 88 - metabolism; Piperazines - pharmacology; Protein Multimerization - drug effects; Real-Time Polymerase Chain Reaction; Signal Transduction; Thiazoles - pharmacology
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djv364

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