Association of toxicity of sorafenib and sunitinib for human keratinocytes with inhibition of signal transduction and activator of transcription 3 (STAT3)

Kazuhiro Yamamoto; Atsushi Mizumoto; Kohji Nishimura; Atsushi Uda; Akira Mukai; Kazuhiko Yamashita; Manabu Kume; Hiroo Makimoto; Toshinori Bito; Chikako Nishigori; Tsutomu Nakagawa; Takeshi Hirano; Midori Hirai

doi:10.1371/journal.pone.0102110

Association of toxicity of sorafenib and sunitinib for human keratinocytes with inhibition of signal transduction and activator of transcription 3 (STAT3)

PLoS One. 2014 Jul 11;9(7):e102110. doi: 10.1371/journal.pone.0102110. eCollection 2014.

Affiliations

¹ Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
² Division of Pharmacokinetics, Kobe University Graduate School of Medicine, Kobe, Japan.
³ Division of Dermatology, Kobe University Graduate School of Medicine, Kobe, Japan.
⁴ Department of Pharmacy, Kobe University Hospital, Kobe, Japan; Division of Pharmacokinetics, Kobe University Graduate School of Medicine, Kobe, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Cell Line, Transformed
Cell Proliferation
Cyclic S-Oxides / pharmacology
Gene Expression Regulation
Humans
Indoles / toxicity*
Inhibitor of Apoptosis Proteins / genetics
Inhibitor of Apoptosis Proteins / metabolism
Keratinocytes / cytology
Keratinocytes / drug effects*
Keratinocytes / metabolism
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / genetics
Mitogen-Activated Protein Kinases / metabolism
Niacinamide / analogs & derivatives*
Niacinamide / toxicity
Phenylurea Compounds / toxicity*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Pyrroles / toxicity*
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / genetics*
STAT3 Transcription Factor / metabolism
Signal Transduction
Sorafenib
Sunitinib
Survivin
Tetrazolium Salts / pharmacology

Substances

2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt
Antineoplastic Agents
BIRC5 protein, human
Cyclic S-Oxides
Indoles
Inhibitor of Apoptosis Proteins
Phenylurea Compounds
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Pyrroles
STAT3 Transcription Factor
STAT3 protein, human
Survivin
Tetrazolium Salts
stattic
Niacinamide
Sorafenib
Mitogen-Activated Protein Kinases
Sunitinib

Grants and funding

This work was supported by a research grant from The Nakatomi Foundation and JSPS KAKENHI (Grant Number 24790156). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.