Hydroxylase Inhibition Selectively Induces Cell Death in Monocytes

Abstract

1000 mM DMOG for time indicated. Densitometry data of phospho-RIPK/pan-RIPK are expressed as mean + SEM of n = 4 independent experiments. In all immunoblots, b-actin was used as positive control. Densitometry data of cIAP1 levels are expressed as mean + SEM of n = 3 independent experiments. Data are expressed as mean percentage of live, apoptotic, and necrotic populations + SEM (n = 4). Statistical analysis was performed using one-or two-way ANOVA, followed by Tukey posttest. *p # 0.05, **p # 0.0, ***p # 0.001, ****p # 0.0001.

Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology

“…deferoxamine, DFO) (Wang & Semenza, 1993), or molecules which compete for 2-oxoglutarate (Mole et al 2003). Modulation of PHD enzyme activity is beneficial in promoting anti-inflammatory responses by selectively inducing cell death in monocytes (Crifo et al 2019), neutrophils (Manresa et al 2019), and enhancing intestinal epithelial barrier function (Cummins et al 2008), in pro-angiogenic responses via the HIF-dependent upregulation of vascular endothelial growth factor (VEGF), offering protection in ischaemic disease (Milkiewicz et al 2004), as well as helping ameliorate anaemia in patients with kidney disease by stimulating erythropoietin (EPO) production and regulating iron absorption and metabolism (Chen et al 2019b,c).…”

“…Modulation of PHD enzyme activity is beneficial in promoting anti‐inflammatory responses by selectively inducing cell death in monocytes (Crifo et al . 2019), neutrophils (Manresa et al . 2019), and enhancing intestinal epithelial barrier function (Cummins et al .…”

The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

“…Furthermore, PHD inhibition enhances the antibacterial activity of skin phagocytes and keratinocytes 20 and boosts mucosal protection during colitis 21 . Notably, dimethyloxalylglycine (DMOG), a prodrug precursor of N -oxalylglycine, which inhibits multiple 2-oxoglutarate (2OG)-dependent oxygenases 22 , including the PHDs, decreases survival of human THP-1 AML cells 23 ; however, the therapeutic significance of selective pharmacological PHD inhibition with consequent HIF-α upregulation in many diseases and malignancies, including AML, remains unknown.…”

Cells and mediators of inflammation as effectors of epithelial repair in the inflamed intestine

“…Data suggest that blood monocytes are conditioned to be proinflammatory before entering into the intestinal inflamed tissue. Furthermore, the pan-hydroxylase inhibitor, DMOG, effective in alleviation of inflammation in model of DSS-colitis, was found also to induce selectively cell death of monocytes, a mechanism that contributes to the anti-inflammatory activity of the drug (109). Over the course of intestinal inflammation, the differentiation of recruited Ly6C hi CCR2 hi monocytes fails to fully reach a mature macrophage stage, but rather reach an immature macrophage phenotype that is able to retain proinflammatory/M1 abilities (104).…”