PLoS ONE (Jan 2014)

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
https://doi.org/10.1371/journal.pone.0102110
Journal volume & issue
Vol. 9, no. 7
p. e102110

Abstract

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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.