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 1.0microM As(III) or 0.5microM 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.
Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA.
Shugo
S
Suzuki
Lora L
LL
Arnold
Karen L
KL
Pennington
Baowei
B
Chen
X Chris
XC
Le
Samuel M
SM
Cohen
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D048708:Cell Growth Processes / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D006651:Histocytochemistry; D011799:Quinazolines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology
D018053:Arsenites; D011799:Quinazolines; C472511:dimethylarsinous acid; D002101:Cacodylic Acid; D066246:ErbB Receptors; C015001:arsenite; D000077156:Gefitinib