The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Abstract

This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25 M. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-(Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer.

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

“…NOX1 knockdown experiments (Fig. 7B) confirmed the crucial role of this protein in the survival of hepatocytes to proapoptotic insults dependent on TGF-␤ or growth factor deprivation as we have described previously in tumoral hepatocytes (16,23,42). Indeed, results presented here indicate that one of the mechanisms for NOX1 to promote survival is via NF-B activation because its knockdown reduced p65 nuclear translocation (Fig.…”

MicroRNA profiling differentiates colorectal cancer according to KRAS status

“…The pathway analysis performed with differentially expressed miRNAs showed the role of the miRNAs in pathways related to NADPH regeneration and GPCR signaling. NADPH is an important component of the NADPH oxidase complex; NADPH oxidases play different roles in cell signaling, gene expression regulation, cell death, differentiation, and growth (Sancho and Fabregat, 2011). NADPH oxidases transmit signals to downstream receptor tyrosine kinases, such as EGFR (Petry et al, 2010), and inhibitors of NADPH oxidases reduce EGFR level (Sancho and Fabregat, 2011).…”

Physiological and pathological functions of NADPH oxidases during myocardial ischemia–reperfusion

“…Although more specific Nox inhibitors have been reported recently, these do not appear to be isoform specific either. VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) was identified originally as an inhibitor of Nox2, but it also inhibits Nox4 (Kleinschnitz, 2010), Nox1 (Sancho, 2011), and Duox (Niethammer, 2009), and GKT137831 (2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c] pyridine-3,6 (2H,5H)-dione) inhibits not only Nox4 but also Nox1 and Nox2 (Jiang, 2012). Thus, despite its potential for treatment of I/R injury and heart failure, to our knowledge, a Nox4-specific inhibitor remains to be developed.…”