Increased expression of inducible nitric oxide synthase (iNOS) in N-nitrosobis(2-oxopropyl)amine-induced hamster pancreatic carcinogenesis and prevention of cancer development by ONO-1714, an iNOS inhibitor

Abstract

Elevated protein expression of inducible nitric oxide synthase (iNOS) has been observed in human pancreatic cancers and therefore, iNOS may play important roles in pancreatic carcinogenesis. This was examined in the present study, using an experimental model with N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. Reverse transcription-polymerase chain reaction analysis demonstrated iNOS expression in a hamster pancreatic cancer cell line as well as in human pancreatic cancer cell lines. Immunohistochemical analysis revealed increased expression of iNOS protein in atypical hyperplasia and ductal adenocarcinomas of the pancreas in BOP-treated hamsters. In addition, iNOS expression was also observed in macrophages and islet cells in pancreatic tissue surrounding tumors. In order to assess the role of iNOS expression in carcinogenesis in the pancreas, the effects of ONO-1714 [(1S, 5S, 6R, 7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane], an iNOS inhibitor, on hamster pancreatic ductal carcinogenesis were investigated. Female Syrian golden hamsters were treated with BOP at 10 mg/kg body wt, four times for 1 week, and 1 week after the last carcinogen treatment, ONO-1714 was administered at doses of 100 and 200 p.p.m. in the diet for 15 weeks. The incidences and multiplicities of atypical hyperplasia and invasive adenocarcinoma and total adenocarcinomas (non-invasive and invasive adenocarcinomas) in the pancreas were significantly lowered by treatment with 200 p.p.m. ONO-1714. Treatment with 100 p.p.m. ONO-1714 also significantly decreased the multiplicities of invasive and total adenocarcinomas. Moreover, treatment with 200 p.p.m. ONO-1714 reduced the number of BOP-induced cholangiocellular tumors. These results suggest that iNOS plays roles in promoting pancreatic carcinogenesis in both early and late stages in hamsters.

Tristetraprolin: a novel mediator of the anticancer properties of resveratrol

“…Nevertheless, studies have found that high concentrations of NO can inhibit the proliferation of tumor cells by blocking DNA synthesis and mitochondrial oxidation, thus exerting anti-tumor effects (Harada et al, 2004). Low concentrations of NO can be converted to peroxynitrite, causing damage to DNA and promoting tumor progression and metastasis (Takahashi et al, 2008). Moreover, the Kleinert group has demonstrated that overexpression of TTP can significantly increase the expression of iNOS in human colon cancer cell line DLD-1 (Fechir et al, 2005).…”

In Vivo SPECT Imaging with 111In-DOTA-c(RGDfK) to Detect Early Pancreatic Cancer in a Hamster Pancreatic Carcinogenesis Model

“…For this purpose, suitable animal models that mimic the clinical situation as closely as possible are ideal tools. The hamster model used in the present study is well established and has been used for numerous studies of pancreatic duct carcinogenesis and its prevention (20,32,33). Because this carcinogenesis model appeared to be suitable for evaluation of the usefulness of imaging agents in the early detection of pancreatic cancer, we investigated the possibility of early and accurate detection of this cancer by combining this model and SPECT with 111 In-DOTA-c(RGDfK).…”

“…For investigating the mechanisms of the development of pancreatic cancer, an experimental pancreatic ductal carcinogenesis model has been established with the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters (19)(20)(21)(22). This model provides unique characteristics that are similar to a sequence of well-characterized morphologic changes in the human pancreatic duct and frequently shows point mutations in codon 12 of the K-ras gene, in accordance with human findings (23,24).…”

Modifying effects of 1,2-dichloropropane on N-nitrosobis(2-oxopropyl)amine-induced cholangiocarcinogenesis in male Syrian hamsters

“…N-nitrosobis(2-oxopropyl)amine (BOP) is a wellknown multiorgan carcinogen in hamsters, inducing tumors in the pancreas, liver, lung, and kidneys (Pour et al, 1978;Furukawa et al, 2003;Takahashi et al, 2008Takahashi et al, , 2011Okamura et al, 2013). The main purpose of the present study was to determine the modifying effects of 1,2-DCP on BOP-induced cholangiocarcinogenesis in male Syrian hamsters.…”

“…The hamster is a useful cholangiocarcinogenesis model (Imray et al, 1992;Thamavit et al, 1993;Blechacz and Gores, 2008;Takahashi et al, 2008). The carcinogenicity of 1,2-DCP in hamsters, however, has not yet been evaluated.…”