Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor.
Epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3, and increased levels of cytokines and growth factors that promote Stat3 activation have been found within psoriatic lesions. K5.Stat3C transgenic mice, in which keratinocytes express a constitutively active Stat3, develop psoriasis-like skin lesions. In this study, we examined whether STA-21, a small Stat3 inhibitor, could be useful in ameliorating the skin lesions not only in the model mouse but also in human psoriasis. Treatment with STA-21 markedly inhibited the cytokine-dependent nuclear translocation of Stat3 in normal human keratinocytes in vitro. Keratinocyte proliferation was inhibited by STA-21 in a dose-dependent manner through downregulation of c-Myc and cyclin D1, whereas involucrin, transglutaminase 1, and keratin 10 levels were upregulated. Topical application of STA-21 abolished the generation of skin lesions in K5.Stat3C mice. Finally, we treated psoriasis patients with STA-21-containing ointment in a nonrandomized study. Psoriatic lesions in six of the eight patients showed improvement after topical STA-21 treatment for 2 weeks. Therefore, we conclude that targeting Stat3 may lead to a therapy for psoriasis.
Miyoshi
Ken
K
Department of Dermatology, Kochi Medical School, Kochi University, Okocho, Nankoku, Japan.
Takaishi
Mikiro
M
Nakajima
Kimiko
K
Ikeda
Mitsunori
M
Kanda
Takashi
T
Tarutani
Masahito
M
Iiyama
Tatsuo
T
Asao
Naoki
N
DiGiovanni
John
J
Sano
Shigetoshi
S
D000287:Administration, Topical; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005240:Feasibility Studies; D006801:Humans; D053550:Keratin-10 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011083:Polycyclic Compounds / Q000008:administration & dosage*; D011498:Protein Precursors / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism
C507493:KRT10 protein, human; D011083:Polycyclic Compounds; D011498:Protein Precursors; C500947:STA-21; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D053550:Keratin-10; C032253:involucrin; D011503:Transglutaminases; C105804:transglutaminase 1