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.
Subject(s)
Antineoplastic Agents/toxicity , Ascorbic Acid/analogs & derivatives , Hand-Foot Syndrome/prevention & control , Keratinocytes/drug effects , Keratinocytes/pathology , Magnesium/pharmacology , Niacinamide/analogs & derivatives , Phenylurea Compounds/toxicity , Apoptosis/drug effects , Ascorbic Acid/pharmacology , Cell Line , Humans , Niacinamide/toxicity , Phosphorylation , RNA, Small Interfering/pharmacology , Reactive Oxygen Species/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Skin/drug effects , Skin/pathology , SorafenibABSTRACT
Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase inhibitors (mTKIs). HFSR can necessitate dose reductions or interruption of therapy owing to its negative effect on the quality of life. Therefore, effective use of mTKIs requires measures to prevent HFSR. We evaluated the effect of prostaglandin E1 (PGE1) on HFSR, because PGE1 is already used to treat bed sores and skin ulcers and has established angiogenic and antiproliferative effects in keratinocytes. We found that the pathogenesis of sorafenib-induced HFSR is characterized by a decrease in levels of a phosphorylated signal transducer and activator of transcription 3 (STAT3). We investigated the effect of PGE1 on the sorafenib-mediated reduction in phosphorylated STAT3 levels in HaCaT human epidermal keratinocytes. In cells treated with sorafenib, phosphorylated STAT3 levels decreased in a concentration-dependent manner, and this effect was blocked in cells treated with sorafenib and PGE1. Furthermore, the expression of phosphorylated STAT3, the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) and survivin decreased in cells pretreated with an inhibitor of cAMP response element binding protein (CREB). Cell viability increased in cells treated with sorafenib and PGE1 compared with that in cells treated with sorafenib alone, and these effects were not observed in STAT3 knockdown HaCaT cells. Collectively, these findings indicate that PGE1 blocks the inhibitory effects of sorafenib on cell growth by maintaining the activity of STAT3 and enhancing the CREB activity. Therefore, PGE1 might represent an effective treatment for the prevention of sorafenib-induced HFSR.
Subject(s)
Alprostadil/pharmacology , Cyclic AMP Response Element-Binding Protein/metabolism , Hand-Foot Syndrome/drug therapy , Keratinocytes/drug effects , Niacinamide/analogs & derivatives , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , STAT3 Transcription Factor/metabolism , Skin/drug effects , Antineoplastic Agents/adverse effects , Cell Line , Cell Proliferation/drug effects , Hand-Foot Syndrome/metabolism , Hand-Foot Syndrome/pathology , Humans , Keratinocytes/metabolism , Keratinocytes/pathology , Niacinamide/adverse effects , Phosphorylation/drug effects , Signal Transduction/drug effects , Skin/metabolism , Skin/pathology , SorafenibABSTRACT
Cordyceps militaris (CM) is gaining attention as a traditional medicinal food, but its molecular biological mechanisms for anti-cancer activity are not identified or clarified. We aimed to elucidate the synthesizing apoptotic effects of CM extracts and to determine the biological effects of CM extract against cordycepin alone in a renal cell carcinoma (RCC) cell line. CM extract showed higher effects of growth inhibition, apoptotic effect, and cell cycle arrest than cordycepin alone. Moreover, CM extract activated extracellular signal-regulated kinase (Erk) highly more than cordycepin alone. We suggest that cordycepin and CM extract induced apoptosis via the activation of Erk dominantly and AMP-activated protein kinase slightly; CM extract has more potent effects on apoptotic effects associated with Erk activation than cordycepin alone.
