Abstract 261: Chemopreventive effects of flavonoids on pancreatic carcinogenesis
Authors: Kato Hiroyuki , Naiki Aya , Suzuki Shugo , Yamashita Yoriko , Takahashi Satoru 
Published: August 2018

Although clinical therapies are being developed for combating pancreatic cancer, its prognosis remains dismal; consequently, chemopreventive strategies may be needed to manage this disease. Luteolin (Lut), a flavone contained in perilla, is one of the most effective antioxidant flavonoids and has demonstrated potential for the treatment of inflammatory and neoplastic disease. Hesperetin (Hes) is a flavone contained in citrus, and the Ohsaki cohort study showed that citrus consumption was correlated with reduced pancreatic cancer (RR=0.62, 95%CI=0.38-1.00) (Int.J.Cancer, 2010: Li.W). However, there are no studies dealing with their antineoplastic effects against pancreatic cancer. In the present study, to assess the chemopreventive effects of Lut and Hes for pancreatic carcinogenesis, 6 week-old syrian golden hamsters were subcutaneously injected with N-nitrsobis(2-oxopropyl)amine four times and then fed Quick Fat Diet (control, n=14) or Quick Fat Diets with Lut 100 ppm (n=13) or Hes 100 ppm, 1000 ppm (n=13,13) for 13 weeks. There were no differences in body weights or liver or kidney weights among the groups. Serum cholesterol was significantly decreased in the Lut group. The incidence and multiplicity of pancreatic cancer was significantly suppressed in the Lut group (Incidence/ Multiplicity: 23%/ 0.23±0.44; P&lt;0.05), but not the Hes groups (100ppm: 54%/ 0.69±0.75, 1000ppm: 62%/ 0.77±0.73), compared to the controls (71%/ 0.93±0.73). The Ki67 labeling index in pancreastic intraepithelial neoplasias (PanINs) was significantly decreased by Lut, but not Hes. Therefore, we focused further investigation on Lut. In vitro, cell proliferation of both hamster (HPD1NR) and human (MiaPaCa, PANC1) pancreatic cancer cell lines was inhibited by Lut in a dose-dependent manner. Multi-blot analysis for phosphorylated proteins related to cell signaling revealed that phosphorylated forms of Stat3 (tyr705) were down-regulated by Lut in MiaPaCa and PANC1 cells. We confirmed them in a dose-dependent manner in the three pancreatic cell lines and also found that Lut down-regulated cyclin D1. In vivo, the nuclear positive proportion of pStat3 (tyr705) in both PanINs and adenocarcinomas was significantly decreased by Lut. Because pStat3 (tyr705) is regulated by cytokines such as Il6, we examined mRNA levels of several cytokines including Il6 in hamster pancreatic tissues. Lut decreased the mRNA expression of Tgfb, Tnfa, Il10, and Il6. Immunohistochemistry of alpha smooth muscle actin revealed that the positive area of activated pancreatic stellate cells, which can produce these cytokines in cancerous tissue, tended to be decreased by Lut. In conclusion, these results indicate that Lut, but not Hes, has potential as a chemopreventive agent for pancreatic cancer and inhibition of pStat3 signaling may be involved in its mechanism of action.

Citation Format: Hiroyuki Kato, Aya Naiki, Shugo Suzuki, Yoriko Yamashita, Satoru Takahashi. Chemopreventive effects of flavonoids on pancreatic carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 261.