Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib

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  • Yamamoto Kazuhiro
    Department of Pharmacy, Kobe University Hospital
  • Shichiri Hiroaki
    Division of Pharmaceutics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine
  • Ishida Takahiro
    R&D Department, Momotani Juntenkan Ltd.
  • Kaku Kenta
    Division of Pharmaceutics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine
  • Nishioka Tatsuya
    Department of Pharmacy, Kobe University Hospital
  • Kume Manabu
    Department of Pharmacy, Kobe University Hospital
  • Makimoto Hiroo
    Department of Pharmacy, Kobe University Hospital
  • Nakagawa Tsutomu
    Department of Pharmacy, Kobe University Hospital Division of Pharmaceutics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine
  • Hirano Takeshi
    Division of Pharmaceutics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine Graduate School of Pharmaceutical Sciences, Health Sciences University of Hokkaido
  • Bito Toshinori
    Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine
  • Nishigori Chikako
    Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine
  • Yano Ikuko
    Department of Pharmacy, Kobe University Hospital Division of Pharmaceutics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine
  • Hirai Midori
    Division of Pharmaceutics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine

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Abstract

<p>Hand–foot skin reaction is recognized as one of the most common adverse events related to multiple tyrosine kinase inhibitors, but an effective prevention method has not been identified. The chief aim of this study was to find a mechanism-based preventive method for the skin toxicity induced by sorafenib using vitamin C derivatives. The effects of ascorbyl-2-phosphate magnesium (P-VC-Mg) on the molecular and pathological changes induced by sorafenib were investigated in human keratinocyte HaCaT cells. The cell growth inhibition and apoptotic effects of sorafenib were attenuated by P-VC-Mg. Moreover, P-VC-Mg inhibited the decrease of signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of apoptosis suppressors treated by sorafenib. HaCaT cells transfected with the STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) combined with P-VC-Mg did not exhibit the attenuation of cell growth inhibition. Interestingly, after exposure to sorafenib in a three dimensional (3D) skin model assay, the basal layer was significantly thickened and the granular and spinous layers became thinner. In contrast, after exposure to sorafenib with P-VC-Mg, the thickness of the basal, granular, and spinous layers was similar to that of the control image. These findings suggest that P-VC-Mg attenuates sorafenib-induced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity.</p>

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