Implication of myeloid differentiation factor 88 inhibitor TJ‐M2010‐5 for therapeutic intervention of hepatocellular carcinoma

Abstract

Aim Myeloid differentiation factor 88 (MyD88) plays a key role in tumor proliferation and metastasis. Targeting MyD88 is a potent strategy in tumor therapy. TJ‐M2010‐5 is a small molecule derivative of aminothiazole and could inhibit dimer formation of MyD88. To explore the potential of TJ‐M2010‐5 in tumor therapy, we determined its antitumor effect and correlate mechanisms of TJ‐M2010‐5 in hepatocellular carcinoma (HCC). Methods The antitumor effect of intratumoral injection of TJ‐M2010‐5 to H22 tumor‐bearing BALB/c mice was observed. Tumor growth was monitored. The expression of MyD88 and Ki‐67 were detected by immunofluorescence. In vitro, the impacts of TJ‐M2010‐5 on proliferation, cell cycle, necrosis, and apoptosis of H22 cells were evaluated. The direct and indirect effects of TJ‐M2010‐5 on macrophages were evaluated using flow cytometry. Results TJ‐M2010‐5 induced both G0/G1 and G1/S phase arrests in HCC cells. Mechanically, downstream activation of MyD88 was suppressed by TJ‐M2010‐5 through the extracellular regulated protein kinase‐1/2/p90 ribosomal S6 kinase/glycogen synthase kinase‐3β signaling pathway. In turn, cyclin‐dependent kinase (CDK)6/cyclin D1 and CDK2/cyclin E complexes were downregulated. More importantly, TJ‐M2010‐5 significantly inhibited tumor growth in mice. Additionally, the portion of antitumor M1 macrophages (F4/80+CD11c+) in the tumor microenvironment were increased after TJ‐M2010‐5 treatment. Together, these data indicate that TJ‐M2010‐5 is a promising therapeutic drug for HCC. Conclusions These results indicate that MyD88 is a feasible target for antitumor treatment and TJ‐M2010‐5 is a qualified candidate for HCC therapy.

Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells

“…MyD88 −/− MDSCs fail to suppress the tumor antigen-specific T cell immune response [26]. Moreover, our previous study proved that the administration of a novel MyD88 inhibitor, TJ-M2010-5 (a patented small-molecule compound synthesized by Dr. Zhou's group), which has been proven to be effective in suppressing the innate immune response in many animal models of diseases (such as hepatocellular carcinoma [27], acute liver injury [28], tracheal, cardiac and skin transplantation [29,30], graft-versus-host disease [31] and myocardial ischemia reperfusion injury [32]), may completely prevent the development of colitis-associated colorectal cancer (CAC) in mice by controlling inflammation and carcinogenesis [33]. Therefore, we investigated the impact of the novel MyD88 inhibitor on the number, phenotype, and function of MDSCs in mice with CAC.…”

Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals

“…An integration , Huang et al, 2021 , Huang et al, 2021 , Liu et al, 2019 , Liu et al, 2019 , World Health Organization, 2022 .…”

Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe?

“…It is conceivable that MyD88 might play a key role in the generation of pro-tumor immunity, and treatment with its inhibitor, TJ-M2010-5, resulted in an increase in the antitumor M1 macrophages (F4/80 CD11c) in the TME and decreased HCC growth. 140 Combining an anti-PD-1 immunotherapeutic agent, nivolumab, with an HDAC inhibitor could both improve the M1 polarization and antitumor activity of anti-PD-1 therapy. 141 An interesting study by Zong et al 142 showed that infiltrated CD68 + human leukocyte antigen-antigen D related (HLA-DR) + M1 macrophages triggered the expression of PD-L1 through activated IL-1β/p65/IRF1 pathway in HCC cells, and they concluded that there was a pro-tumor role for M1 TAMs.…”