To facilitate high throughput screening, we performed our screen

To facilitate high throughput screening, we performed our screen entirely in human hepatoma cells (HepG2). As hepatocellular carcinoma cells exhibit increased signaling by FGF, PDGF, and VEGF, this may have biased our results to identify antagonists of growth factor signaling. Others, however, have used small scale screening of kinase inhibitors to demonstrate that hepatocyte growth

factor (HGF) and epidermal growth factor (EGF) reduce BMP-stimulated Hepcidin expression in a mitogen-activated ERK kinase/extracellular signal-related kinase (MEK/ERK) dependent manner in primary mouse hepatocytes [24]. HGF’s inhibitory activity on Hepcidin expression can be suppressed by pre-treatment with small molecule inhibitors of Met (PHA665752), MEK1/2 (U0126), or PI3Kinase (LY2940021) [24]. Furthermore intraperitoneal injection of EGF in wild type mice reduces the induction of Hepcidin expression in response to

iron loading [24]. Given these findings, we propose that SU6668, GTP 14564, AG1296, AS252424, 10058-F, and pterostilbene enhance Hepcidin transcript levels in HepG2 cells by inhibiting growth-factor dependent signaling. One of the most interesting findings in the screen is that the nonselective BI 6727 mouse histone deacetylase (HDAC) inhibitor, vorinostat, is a potent stimulant of Hepcidin expression. These data are consistent with the finding that histone acetylation increases Hepcidin expression  [4], [46] and [47]. In particular, post-translational modification of Histone H3, one of the core proteins of the nucleosome, AMP deaminase regulates transcription and chromatin condensation [48]. Transfection of Smad4 into Smad4-null hepatocytes increases binding of Histone 3 acetylated at lysine 9 (H3K9) to the

Hepcidin promoter [4]. Histone acetylation also appears to affect Stat3 binding to the Hepcidin promoter. Hepatitis C viral infection of cultured hepatoma cells causes hypoacetylation of histones and decreased Hepcidin expression, while treatment with the pan-HDAC inhibitor, trichostatin A, increases Stat3 binding to the Hepcidin promoter [46] and enhances Hepcidin expression  [46] and [47]. Vorinostat has been approved for the treatment of refractory cutaneous T-cell lymphoma [49] and thus may be amenable to clinical investigation in patients with iron overload syndromes who produce inappropriately low levels of Hepcidin. The anti-inflammatory drugs, amlexanox, lansoprazole, and leflunomide each increased Hepcidin expression and ID3 expression in the screen. Amlexanox is an anti-allergic drug that binds the cytoskeletal protein S100A13 and inhibits heat shock-induced release of FGF1 [50].

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