Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib
Kazuhiro Yamamoto1, Hiroaki Shichiri2, Takahiro Ishida3
1Department of Pharmacy, Kobe University Hospital.
Abstract:
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.
Insights
Vitamin C derivatives, specifically ascorbyl-2-phosphate magnesium (P-VC-Mg), can prevent skin toxicity caused by sorafenib. This vitamin C derivative maintains signal transducer and activator of transcription 3 (STAT3) activity, reducing cell death and skin damage.
Area of Science:
- Dermatology
- Oncology
- Biochemistry
Background:
- Hand-foot skin reaction is a common side effect of tyrosine kinase inhibitors like sorafenib.
- No effective prevention methods for this skin toxicity currently exist.
Purpose of the Study:
- To investigate a mechanism-based preventive method for sorafenib-induced skin toxicity using vitamin C derivatives.
- To evaluate the effects of ascorbyl-2-phosphate magnesium (P-VC-Mg) on molecular and pathological changes induced by sorafenib.
Main Methods:
- Experiments were conducted on human keratinocyte (HaCaT) cells and a 3D skin model.
- Assessed cell growth inhibition, apoptosis, and signal transducer and activator of transcription 3 (STAT3) phosphorylation.
- Utilized STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) for mechanistic studies.
Main Results:
- P-VC-Mg attenuated sorafenib-induced cell growth inhibition and apoptosis in HaCaT cells.
- P-VC-Mg maintained STAT3 phosphorylation and the expression of apoptosis suppressors that were reduced by sorafenib.
- In a 3D skin model, P-VC-Mg prevented sorafenib-induced pathological changes in skin layers.
Conclusions:
- P-VC-Mg mitigates sorafenib-induced apoptosis and skin damage in human keratinocytes and a 3D skin model.
- The protective effect of P-VC-Mg is mediated by maintaining STAT3 activity.
