1α,25-Dihydroxyvitamin-D3-3-Bromoacetate Regulates AKT/mTOR Signaling Cascades: A Therapeutic Agent for Psoriasis

Abstract

The efficacy of 1α,25-dihydroxyvitamin D3 (Vit-D) limits its topical use despite its profound effects on cellular differentiation, proliferation, and immunomodulation. Therefore, in search for a more effective analog of Vit-D, in this study we have evaluated the antiproliferative and proapoptotic effects of 1α,25-dihydroxyvitamin D3-3-bromoacetate (BE). Proliferation and apoptosis studies in normal human epidermal keratinocytes (NHEKs) were conducted by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), CFSE (carboxy fluorescein succinimidyl ester) dilution, and Annexin V assays. Western blot analysis and real-time PCR were performed to determine its effect on signal transduction. A reconstructed human epidermis (RHE) model was used to further validate the therapeutic role of BE in psoriasis. BE was significantly more potent than an equivalent concentration of Vit-D in inhibiting growth and survival of human keratinocytes. The antimitotic effect was found to be due to the inhibition of phosphorylation of serine/threonine protein kinase (AKT) and its downstream target, mammalian target of rapamycin (mTOR). In the RHE model, BE reversed IL-22-induced psoriasiform changes more effectively than Vit-D. Interestingly, BE inhibited the IL-22-induced gene expression of AKT1, MTOR, chemokines [IL-8 and RANTES (regulated upon activation, normal T-cell expressed and secreted)], and psoriasin (S100A7) more significantly than Vit-D. These results suggest the potential of BE as a prospective therapeutic agent for psoriasis.

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…428, a validation study with three different RhE models -EpiDerm™, EpiSkin™ and SkinEthic™ -indicated their general suitability for in vitro absorption studies, both in infinite and finite dose experiments (Schafer-Korting et al, 2008). Though the permeability rate determined using RhEs seems to exceed that found using ex Mitra et al, 2013;Eves et al, 2003;Li et al, 2011;Tjabringa et al, 2008).…”

Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation

“…Interestingly, IL-22 is not only able to activate mTOR signaling but also induces the expression of mTOR mRNA [31]. Strong activation of mTORC1 in the basal compartment seems to be at least partially involved in proliferative control.…”

Vitamin D and the Pathophysiology of Inflammatory Skin Diseases

“…Calcipotriol was found to suppress Th17-induced psoriasin and koebnerisin in psoriatic skin [84]. In an epidermal reconstructed model of psoriasis, Datta Mitra et al [85] showed that 1α,25-dihydroxyvitamin D 3 -3-bromoacetate, a vitamin D analog, has a more potent antiproliferative action compared to 1,25(OH) 2 D 3 . He showed that bromoacetate reverses the psoriasiform changes induced by IL-22 in the reconstructed epidermal model by inhibiting the expression of AKT1, MTOR, chemokines (IL-8 and RANTES) and psoriasin (S100A7).…”