Effects of an epidermal growth factor receptor inhibitor on arsenic associated toxicity in the rat bladder epithelium

Arsenite (As^III), an inorganic arsenical, is a known human carcinogen, inducing tumors of the skin, urinary bladder and lung. It is known to be metabolized to organic methylated arsenicals in vivo. As^III has been reported to have the ability to up-regulate the epidermal growth factor receptor (EGFR)-associated pathway in epithelial cells, including human urothelial cells in vitro. EGFR is a cell-surface receptor belonging to the ErbB family of receptor tyrosine kinases, and the EGFR-associated signaling pathway has been reported to play an important role in carcinogenesis and cancer progression, including in bladder cancer. In this study, we investigated the growth effects of As^III and an organic trivalent arsenical, dimethylarsinous acid (DMA^III), and the effects of co-exposure of gefitinib, an EGFR inhibitor, with As^III to a rat urothelial cell line (MYP3). We also investigated the effects of co-administration of dietary As^III and gefitinib in vivo. In vitro, concentrations of 1.0 μM As^III or 0.5 μM DMA^III induced cytotoxicity. However, lower concentrations of As^III treatment had a slight mitogenic growth effect whereas lower concentrations of DMA^III did not. Gefitinib blocked As^III-induced cell growth in vitro. In vivo, a high dose of gefitinib alone induced slight urothelial cytotoxicity, and did not reduce cytotoxicity and regenerative cell proliferation when co-administered with As^III. The majority of arsenic metabolites present in the urine of As^III-treated rats were organic arsenicals, mainly dimethylarsinic acid (DMA^V). As^III was also present, and its concentration was higher than the concentration required to produce cytotoxicity in vitro. These data suggest that an EGFR inhibitor has the ability to block As^III-induced cell proliferation in vitro but not in vivo in a short-term study.