Radiation-induced surge of macrophage foam cell formation, oxidative damage, and cytokine release is attenuated by a nanoformulation of curcumin

Purpose: We examined the potential of a dendrosomal nanoformulation of curcumin (DNC) for intervention of ionizing radiation (IR)-induced damage (particularly leading to atherosclerosis), employing an irradiated THP-1 macrophage model.Materials and methods: Differentiated THP-1 macrophages were irradiated and treated with curcumin or DNC nanoformulation (and oxidized low density lipoprotein, ox-LDL, to promote foam cells). Chemical, biochemical, and genetics tools including viability and apoptosis, multiple ELISA, real-time PCR, Western blotting, enzyme activity, and fluorimetry assays were employed to illustrate IR damage as well as the DNC intervention potential.Results: DNC per se at 10 M exerted no cytotoxic effects on macrophages. However, it caused apoptosis in 2Gy-irradiated macrophages which were treated with ox-LDL, chiefly through a caspase-dependent pathway involving caspase-3. Concurrently, 10 M DNC prevented the IR-induced rise in lipid accumulation (72% decrease compared to IR control, p <.0001), dil-oxLDL uptake (78% decrease, p <.005), protein and mRNA expression of cholesterol influx genes, CD36 and SR-A, NF-B activation (81% less binding activity, p <.001; and lower nuclear presence of p65), cytokine (monocyte chemoattractant protein-1 and interleukin-1) release, reactive oxygen species (ROS), and oxidative damage to DNA (37% decrease in 8-OHdG, p <.05) and lipids (62% decrease in 8-isoprostane, p <.005). DNC facilitated the uptake of curcumin in irradiated macrophages, increased glutathione peroxidase expression and activity, restored glutathione (GSH) level, and upregulated the expression of a cholesterol efflux gene, ABCA1. Two other antioxidants, resveratrol and N-acetyl cycteine (NAC), could simulate some of the beneficial effects of DNC against IR-induced CD36 expression and lipid accumulation, which were obviated by buthionine sulfoximine (BSO) pre-treatment of macrophages. However, some modulatory effects of DNC, particularly on lipid accumulation and the expression of SR-A and ABCA1 genes, seemed to be independent of its antioxidant effect, since they were still observed in BSO-pretreated macrophages, depleted of GSH.Conclusions: DNC treatment suppresses IR-induced oxidative damage, inflammation, and foam cell formation in macrophages through multiple mechanisms.