title: Prostaglandin E1reduces the keratinocyte toxicity of sorafenib by maintaining signal transducer and activator of transcription 3 (STAT3) activity and enhancing the cAMP response element binding protein (CREB) activity.
abstract: Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase inhibitors (mTKIs). HFSR can necessitate dose reductions or interruption of therapy owing to its negative effect on the quality of life. Therefore, effective use of mTKIs requires measures to prevent HFSR. We evaluated the effect of prostaglandin E1(PGE1) on HFSR, because PGE1is already used to treat bed sores and skin ulcers and has established angiogenic and antiproliferative effects in keratinocytes. We found that the pathogenesis of sorafenib-induced HFSR is characterized by a decrease in levels of a phosphorylated signal transducer and activator of transcription 3 (STAT3). We investigated the effect of PGE1on the sorafenib-mediated reduction in phosphorylated STAT3 levels in HaCaT human epidermal keratinocytes. In cells treated with sorafenib, phosphorylated STAT3 levels decreased in a concentration-dependent manner, and this effect was blocked in cells treated with sorafenib and PGE1. Furthermore, the expression of phosphorylated STAT3, the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) and survivin decreased in cells pretreated with an inhibitor of cAMP response element binding protein (CREB). Cell viability increased in cells treated with sorafenib and PGE1compared with that in cells treated with sorafenib alone, and these effects were not observed in STAT3 knockdown HaCaT cells. Collectively, these findings indicate that PGE1blocks the inhibitory effects of sorafenib on cell growth by maintaining the activity of STAT3 and enhancing the CREB activity. Therefore, PGE1might represent an effective treatment for the prevention of sorafenib-induced HFSR.
authors.affiliation: Division of Pharmaceutics, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shichiri
authors.affiliation: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Electronic address: yamakz@med.kobe-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Educational Center for Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1, Motoyamakitamachi, Higashinada-ku, Kobe-shi, Hyogo, 658-8558, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Tokura
authors.affiliation: R&D Department, Momotani Juntenkan LTD, 1-4-1, Uemachi, Chuo-ku, Osaka, 540-0005, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Uda
authors.affiliation: Division of Dermatology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Bito
authors.affiliation: Division of Dermatology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Nishigori
authors.affiliation: Division of Pharmaceutics, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Division of Pharmaceutics, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.affiliation: Division of Pharmaceutics, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Hirai
mesh_terms: D000527:Alprostadil / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D060831:Hand-Foot Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000009:adverse effects*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib; D000527:Alprostadil
keywords: Hand-foot skin reaction; Keratinocyte; Prostaglandin E(1); STAT3; Sorafenib