title: 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.
authors: IM/Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Sacramento, California, USA.
authors: Ananya
authors: A
authors: Datta Mitra
authors: Siba P
authors: SP
authors: Raychaudhuri
authors: Christine J
authors: CJ
authors: Abria
authors: Anupam
authors: A
authors: Mitra
authors: Rebecca
authors: R
authors: Wright
authors: Rahul
authors: R
authors: Ray
authors: Smriti
authors: S
authors: Kundu-Raychaudhuri
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D000078404:Epidermal Cells; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014807:Vitamin D / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology; D000097043:Interleukin-22
chemical_list: D002117:Calcitriol; D018946:Chemokine CCL5; D016209:Interleukin-8; D007378:Interleukins; D051057:Proto-Oncogene Proteins c-akt; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D058570:TOR Serine-Threonine Kinases; D014807:Vitamin D; D014815:Vitamins; D000097043:Interleukin-22; C104313:1,25-dihydroxyvitamin D3-3-bromoacetate; C508606:CXCL8 protein, human; C089242:S100A7 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human