Epidermal growth factor receptor inhibition with erlotinib partially prevents cisplatin-induced nephrotoxicity in rats.

Yukihiro Wada,Yoshihiro Kuno,Taihei Suzuki,Takanori Shibata,Masayuki Iyoda,Kei Matsumoto,Tomohiro Saito,Yuki Shindo-Hirai,Yasutaka Yamamoto,Ken Iseri,Jean-Claude Dussaule

doi:10.1371/journal.pone.0111728

Yukihiro Wada, Yoshihiro Kuno + Show 9 more

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https://doi.org/10.1371/journal.pone.0111728

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Journal: PloS one	Publication Date: Nov 12, 2014
Citations: 30	License type: CC BY 4.0

Affiliation: Showa University

Abstract

The effects of blocking the epidermal growth factor receptor (EGFR) in acute kidney injury (AKI) are controversial. Here we investigated the renoprotective effect of erlotinib, a selective tyrosine kinase inhibitor that can block EGFR activity, on cisplatin (CP)-induced AKI. Groups of animals were given either erlotinib or vehicle from one day before up to Day 3 following induction of CP- nephrotoxicity (CP-N). In addition, we analyzed the effects of erlotinib on signaling pathways involved in CP-N by using human renal proximal tubular cells (HK-2). Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells. Erlotinib-treated rats had a significant reduction of renal cortical mRNA for profibrogenic genes. The Bax/Bcl-2 mRNA and protein ratios were significantly reduced by erlotinib treatment. In vitro, we observed that erlotinib significantly reduced the phosphorylation of MEK1 and Akt, processes that were induced by CP in HK-2. Taken together, these data indicate that erlotinib has renoprotective properties that are likely mediated through decreases in the apoptosis and proliferation of tubular cells, effects that reflect inhibition of downstream signaling pathways of EGFR. These results suggest that erlotinib may be useful for preventing AKI in patients receiving CP chemotherapy.

Highlights

Cisplatin (CP) is a frontline chemotherapeutic agent used in the treatment of solid tumors [1,2]
epidermal growth factor receptor (EGFR) is displayed on the cell surface, where the receptor is activated by binding of its ligands, including EGF, heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor-a (TGF-a), amphiregulin, betacellulin, epiregulin, and the neuregulins [7,8]
We show that erlotinib has preventive effects in experimental CP- nephrotoxicity (CP-N); this preventive role is mediated by reductions in tubular cell proliferation and apoptosis, but not by reductions in inflammation in tubules

Summary

Introduction

Cisplatin (CP) is a frontline chemotherapeutic agent used in the treatment of solid tumors [1,2]. An important side effect of CP administration is acute kidney injury (AKI); approximately onethird of patients show evidence of renal dysfunction following CP treatment [3,4]. CP induces necrosis as well as apoptosis in these cells, leading to AKI [4,5]. Hoffmann-La Roche, Basel, Switzerland), a selective tyrosine kinase inhibitor that inhibits the epidermal growth factor receptor (EGFR), has been demonstrated to be highly active in patients with non-small cell lung cancer, pancreatic cancer, and several other types of cancer [6]. Upon activation by its growth factor ligands, EGFR autophosphorylates at several tyrosine residues. This autophosphorylation elicits downstream activation and signaling. This downstream signaling initiates several signal transduction cascades, principally the mitogenactivated protein kinase (MAPK) and the phosphoinositide 3kinase (PI3K)-Akt pathways, which act to regulate cellular processes such as proliferation, apoptosis, migration, and differentiation [8,9,10]

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