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

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 sorafenibinduced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity.Key words vitamin C; multi-targeted tyrosine kinase inhibitor; hand-foot skin reaction (HFSR); ascorbic acidThe treatment for metastasis renal cell carcinoma has led to significant advances by molecular targeted drugs. However, some safety issues have recently emerged. In particular, adverse reactions induced by multiple tyrosine kinase inhibitors (mTKIs) are some of the major causes for the interruption of therapy involving these drugs. 1) Dermatological adverse events, also called hand−foot skin reaction, manifest topically in the palmar and plantar regions, and the pathological mechanism underlying these events is unclear. Because there are few treatment options for renal cell carcinoma and hepatocellular carcinoma, the success of therapy is determined by the length of efficient treatment and the management of adverse reactions. Therefore, appropriate management of the side effects will lead to an improvement in not only the QOL, but also the outcome of therapy 2,3) Although the dermatological adverse reactions induced by mTKIs are recognized as serious problems in clinical practice, a preventive method based on the pathological mechanism of these drugs has not been established.Previously, we reported that the inhibition of signal transducer and activator of transcription 3 (STAT3) contributes to the mechanism for keratinocyte toxicity induced by mTKIs, 4) and that the development of hand-foot skin reaction induced by mTKIs is associated with STAT3 polymorphisms. 5)STAT3 is a well-known transcriptional factor that regulates ce...

Safety and Efficacy of Bis-Glyceryl Ascorbate (Amitose DGA) to Prevent Hand-Foot Skin Reaction in Patients With Renal Cell Carcinoma Receiving Sunitinib Therapy: Protocol for a Phase I/II, Uncontrolled, Single-Arm, Open-Label Trial

“…We have reported the effects of ascorbic acid derivatives on keratinocyte toxicity induced by multiple-TKIs in vitro [13]. We verified these effects using an animal-testing alternative, consisting of a reconstructed human epidermal model in vitro.…”

“…We recently reported on ascorbyl-2-phosphate magnesium (P-VC-Mg), a highly permeable ascorbic acid derivative; we found that it could relieve multiple-TKI-induced keratinocyte growth inhibition and pathological changes in human keratinocyte cells in a 3D skin model, mediating signal transducer and activator of transcription 3 phosphorylation levels [13,14]. This report suggested that specific ascorbic acid derivatives can prevent multiple-TKI-induced HFSR.…”

Sunitinib decreases the expression of KRT6A and SERPINB1 in 3D human epidermal models

“…Our previous study suggested that an 3D epidermal model treated with multiple TKIs is applicable to the study of HFSR in vitro model using pathology images. 14 is associated with the functional mechanism of sunitinib. 15,16 This is the first report to identify sunitinib-induced molecular changes in cornifying factors in human keratinocytes in a 3D epidermal model.…”

“…In this study, we demonstrated that, in a 3D epidermal model, sunitinib decreased the levels of cornifying factors related to normal keratinization. Our previous study suggested that an 3D epidermal model treated with multiple TKIs is applicable to the study of HFSR in vitro model using pathology images 14 . These changes in expression might be regulated by the MAPK signalling pathway, which is associated with the functional mechanism of sunitinib 15,16 .…”

Apatinib-Induced Hand–Foot Skin Reaction in Chinese Patients With Liver Cancer

“…Moreover, a Japanese doctor, Yamamoto ( 59 ), is now leading a clinical study that aims to put forward the application of ascorbyl-2-phosphate magnesium (P-VC-Mg), a cosmetic product, for the treatment of HFSR. Although no results were available yet, his preliminary experimental data ( 60 ) have indicated that this highly permeable ascorbic acid derivative could confront against sorafenib-induced hyperproliferation of keratinocytes in a 3D skin model.…”