Hepatology research : the official journal of the Japan Society of Hepatology · 2019
Implication of myeloid differentiation factor 88 inhibitor TJ-M2010-5 for therapeutic intervention of hepatocellular carcinoma.
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Liu Jing, Zhang Xue, Wang Haizhou, Zhang Meng, Peng Yanan, Li Mingqiang, Xie Lin, Jiang Fengchao, Gong Yiping, Zhao Qiu, Zhou Ping
Аннотация
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.
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.