Combined treatment with Vitamin E and gefitinib has synergistic effects to inhibit TGF-β1-induced renal fibroblast proliferation

Abstract

Renal fibroblast proliferation is key in renal fibrosis and chronic kidney disease. Transforming growth factor-β1 (TGF-β1) has been demonstrated to be an important factor that induces cell proliferation in renal fibroblasts. Epidermal growth factor receptor (EGFR) is also recognized as a factor promoting renal fibroblast proliferation. In addition, mitogen-activated protein kinase signaling pathways are associated with TGF-β1-and EGFR-induced cell proliferation. Gefitinib, an EGFR tyrosine kinase inhibitor, is predominantly used as an anti-tumor therapeutic agent in clinical therapeutic strategies. However, gefitinib has been suggested to exert anti-proliferative effects on renal fibroblasts, however, high-dose gefitinib may result in serious side effects. The present study aims to determine whether low-dose gefitinib reduces gefitinib-induced side effects and maintains the anti-proliferative effects on renal fibroblasts. TGF-β1 promotes cell proliferation in renal fibroblasts, and the current study demonstrates that low-dose gefitinib treatment exhibits anti-proliferative effects similar to those of high-dose gefitinib treatment. Thus, although high-dose gefitinib is a conventional anti-tumor drug, low-dose gefitinib may be of use in renal fibrosis treatment. Furthermore, the present study demonstrates that a combined treatment with low-dose gefitinib and vitamin E has synergistic effects that reduce TGF-β1-induced fibroblast proliferation, cell-cycle arrest and the ERK phosphorylation pathway.