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Carcinogenesis Advance Access published online on April 21, 2007
Carcinogenesis, doi:10.1093/carcin/bgm095
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Suppression of N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamsters by pioglitazone, a ligand of peroxisome proliferator-activated receptor {gamma}

Yoshito Takeuchi1, Mami Takahashi1, Katsuhisa Sakano1, Michihiro Mutoh1, Naoko Niho1, Masafumi Yamamoto1, Hidetaka Sato2, Takashi Sugimura1 and Keiji Wakabayashi1,3

1 Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
2 Department of Biological Safety Research, Japan Food Research Laboratories, Bunkyo 2-3, Chitose-shi, Hokkaido 066-0052, Japan

3 To whom correspondence should be addressed. E-mail: kwakabay{at}gan2.res.ncc.go.jp

Fat intake and obesity are positively correlated with pancreatic cancer in humans. N-Nitrosobis(2-oxopropyl)amine (BOP) induces pancreatic ductal adenocarcinomas limited to Syrian golden hamsters, other rodents not being susceptible. In the present study, we found markedly high levels of serum triglycerides and total cholesterol in Syrian golden hamsters, but not C57BL/6 mice, ICR mice, F344 rats and Wistar rats. Consistent with this, lipoprotein lipase (LPL) activities in the liver were lower in hamsters compared to mice and rats. To examine effects of pioglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligand, on LPL expression, serum lipid levels and pancreatic cancer development, six-week-old female Syrian golden hamsters were subcutaneously injected with BOP (10 mg/kg body weight) four times in a week and thereafter fed a diet containing 800 ppm pioglitazone for 22 weeks. The treatment elevated LPL mRNA expression in the liver and significantly improved hyperlipidemia, with serum levels of triglyceride and total cholesterol being decreased to 62% and 71%, respectively, of the control values. Concurrently, the incidence and multiplicity of pancreatic ductal adenocarcinomas were significantly decreased by pioglitazone in comparison with the controls (38% vs. 80%, P < 0.01 and 0.55 ± 0.15 vs. 1.37 ± 0.22, P < 0.01, respectively). The suppression rates were grater in invasive adenocarcinomas than non-invasive ones. The incidence of cholangiocellular carcinomas was also reduced. Thus, suppression of pancreatic adenocarcinoma development by pioglitazone is possibly associated with improvement in the serum lipid profile, and hyperlipidemia could be an enhancing factor for development of pancreatic cancer in hamsters.

Key Words: Pancreatic cancer • Hyperlipidemia • Hamster • BOP • Pioglitazone

Received December 25, 2006; revised March 15, 2007; accepted April 11, 2007.


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M. Takahashi, T. Kitahashi, R. Ishigamori, M. Mutoh, M. Komiya, H. Sato, Y. Kamanaka, M. Naka, T. Maruyama, T. Sugimura, et al.
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
Carcinogenesis, August 1, 2008; 29(8): 1608 - 1613.
[Abstract] [Full Text] [PDF]


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