2-5-dimethylcelecoxib and Liver-Neoplasms

2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression of programmed death-ligand 1 on hepatocellular carcinoma (HCC) cells to prevent tumor progression. However, the effect and mechanism of DMC on HCC infiltrating immune cells remain unclear.. In this study, single-cell-based high-dimensional mass cytometry was performed on the tumor microenvironment of HCC mice treated with DMC, celecoxib and MK-886 (a known mPGES-1 inhibitor). Moreover, 16S ribosomal RNA sequencing was employed to analyze how DMC improved the tumor microenvironment of HCC by remodeling the gastrointestinal microflora.. We found that (1) DMC significantly inhibited the growth of HCC and improved the prognosis of the mice, and this depended on the stronger antitumor activity of natural killer (NK) and T cells; (2) compared with celecoxib and MK-886, DMC significantly enhanced the cytotoxic and stem-like potential, and inhibited exhaustion of NK and T cells; (3) mechanistically, DMC inhibited the expression of programmed cell death protein-1 and upregulated interferon-γ expression of NK and T cells via the gastrointestinal microbiota (Bacteroides acidifaciens, Odoribacter laneus, and Odoribacter splanchnicus)-AMPK-mTOR axis.. Our study uncovers the role of DMC in improving the tumor microenvironment of HCC, which not only enriches the relationship between the mPGES-1/prostaglandin E2 pathway and the antitumor function of NK and T cells, but also provide an important strategic reference for multitarget or combined immunotherapy of HCC.Cite Now.

Topics: AMP-Activated Protein Kinases; Animals; Carcinoma, Hepatocellular; Celecoxib; Dinoprostone; Gastrointestinal Microbiome; Liver Neoplasms; Mice; T-Cell Exhaustion; Tumor Microenvironment

As the occurrence and development of HCC are often accompanied by inflammation, the combination of sorafenib with other therapeutic drugs, especially anti-inflammatory drugs, is one of the directions to be explored at present. Our previous research has been focused on the anti-inflammatory drug 2,5-dimethylcelecoxib (DMC), whether DMC combined with sorafenib could elevate the effect of inhibiting HCC deserves further exploration. In this study, we found that DMC induced CYP3A5 expression in HCC cells in a time-dependent and concentration dependent manner. We observed that sorafenib inhibited CYP3A5 expression in liver cancer cells, and activated the phosphorylation of Akt. Upregulated CYP3A5 and DMC treatment enhanced the ability of sorafenib to inhibit migration. The combination of DMC with sorafenib had a synergistic effect of enhancing drug sensitivity (CI < 1), meanwhile, inhibited the proliferation and promoted apoptosis of HCC. Activation of the AMPK pathway and inhibition of the PI3K/Akt pathway were observed in cells treated with DMC in combination with sorafenib and could be reverted by an AMPK pathway inhibitor. Our findings suggest that DMC induces CYP3A5 expression and enhances the anticancer effect of sorafenib by activating AMPK, which would be a novel strategy for drug combination to prevent drug resistance.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cytochrome P-450 CYP3A; Drug Interactions; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Sorafenib; Sulfonamides

2,5-dimethylcelecoxib (DMC) is a targeted inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), a key enzyme in the PGE2 synthesis pathway of inflammatory mediators. Previous studies have confirmed that DMC can inhibit the growth of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, it is not known whether DMC is involved in the changes of tumor immune microenvironment.. In this study, we explored the effects of DMC on HBV-related HCC immune microenvironment, and deeply analyzed its unique effect and mechanism on programmed death receptor 1 (PD-1)/and its ligand 1 (PD-L1) pathway.. Our results uncover a role for DMC in promoting HBV-related HCC immune microenvironment, which not only enrich the relationship between inflammatory factors (mPGES-1/PGE2 pathway) and immunosuppression (PD-L1), but also provide an important strategic reference for multitarget or combined immunotherapy of HBV-related HCC.

Topics: Animals; Carcinoma, Hepatocellular; Drug Therapy; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms; Mice; Pyrazoles; Sulfonamides; Tumor Microenvironment; Ubiquitination