Yamamoto Kazuhiro, Shichiri Hiroaki, Ishida Takahiro, Kaku Kenta, Nishioka Tatsuya, Kume Manabu, Makimoto Hiroo, Nakagawa Tsutomu, Hirano Takeshi, Bito Toshinori, Nishigori Chikako, Yano Ikuko, Hirai Midori
Department of Pharmacy, Kobe University Hospital.
Division of Pharmaceutics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine.
Biol Pharm Bull. 2017;40(9):1530-1536. doi: 10.1248/bpb.b17-00386.
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.
手足皮肤反应被认为是与多种酪氨酸激酶抑制剂相关的最常见不良事件之一，但尚未确定有效的预防方法。本研究的主要目的是使用维生素C衍生物找到一种基于机制的预防索拉非尼诱导的皮肤毒性的方法。在人角质形成细胞HaCaT细胞中研究了抗坏血酸-2-磷酸镁（P-VC-Mg）对索拉非尼诱导的分子和病理变化的影响。P-VC-Mg减弱了索拉非尼的细胞生长抑制和凋亡作用。此外，P-VC-Mg抑制了索拉非尼处理后信号转导和转录激活因子3（STAT3）磷酸化的降低以及凋亡抑制因子的表达。转染了STAT3显性阴性形式（STAT3DN）和STAT3小干扰RNA（siRNA）并联合P-VC-Mg的HaCaT细胞未表现出细胞生长抑制的减弱。有趣的是，在三维（3D）皮肤模型试验中暴露于索拉非尼后，基底层明显增厚，颗粒层和棘层变薄。相比之下，在暴露于索拉非尼和P-VC-Mg后，基底层、颗粒层和棘层的厚度与对照图像相似。这些发现表明，P-VC-Mg通过维持STAT3活性减弱了索拉非尼诱导的人角质形成细胞和3D皮肤模型中的细胞凋亡和病理变化。
