title: Association of toxicity of sorafenib and sunitinib for human keratinocytes with inhibition of signal transduction and activator of transcription 3 (STAT3).
abstract: Hand-foot skin reaction is a most common multi-kinase inhibitor-related adverse event. This study aimed to examine whether the toxicity of sorafenib and sunitinib for human keratinocytes was associated with inhibiting signal transduction and activator of transcription 3 (STAT3). We studied whether STAT3 activity affects sorafenib- and sunitinib-induced cell growth inhibition in HaCaT cells by WST-8 assay. Stattic enhanced the cell-growth inhibitory and apoptotic effects of sorafenib and sunitinib. HaCaT cells transfected with constitutively-active STAT3 (STAT3C) were resistant to the sorafenib- and sunitinib-induced cell growth inhibition. STAT3 activity decreased after short-term treatment with sorafenib and sunitinib in a dose-dependent manner and recovered after long-term treatment with sorafenib and sunitinib at low doses. Moreover, the expression of survivin and bcl-2 decreased after treatment with sorafenib and sunitinib was concomitant with variations in STAT3 activity. Sorafenib-induced STAT3 inhibition was mediated by regulation via MAPK pathways in HaCaT cells, while sunitinib-induced STAT3 inhibition was not. Thus, STAT3 activation mediating apoptosis suppressors may be a key factor in sorafenib and sunitinib-induced keratinocyte cytotoxicity.
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Division of Pharmacokinetics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizumoto
authors.affiliation: Division of Pharmacokinetics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Uda
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mukai
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kume
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Makimoto
authors.affiliation: Division of Dermatology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Bito
authors.affiliation: Division of Dermatology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Nishigori
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan; Division of Pharmacokinetics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan; Division of Pharmacokinetics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Pharmacy, Kobe University Hospital, Kobe, Japan; Division of Pharmacokinetics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Hirai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D003499:Cyclic S-Oxides / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000633:toxicity; D010671:Phenylurea Compounds / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000633:toxicity*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D000077210:Sunitinib; D000077022:Survivin; D013778:Tetrazolium Salts / Q000494:pharmacology
chemical_list: C476329:2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D003499:Cyclic S-Oxides; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D013778:Tetrazolium Salts; C517409:stattic; D009536:Niacinamide; D000077157:Sorafenib; D020928:Mitogen-Activated Protein Kinases; D000077210:Sunitinib