Abstract 2589: Novel chemopreventive combinatorial regimen significantly suppresses NF-kB and PI3-kinase/Akt pathways in the Syrian golden hamster pancreatic cancer model

Abstract

Pancreatic cancer caused 40,000 deaths in 2010 and is currently ranked as the fourth leading cause of deaths in the United States. Due to poor prognosis of this disease, it is imperative that chemopreventive strategies be developed to control the formation of the initial neoplastic lesions. We have previously reported the effectiveness of a low dose combination regimen of aspirin, curcumin and sulforaphane (ACS) on MIA-PaCa-2 and Panc-1 pancreatic cancer cell lines. The objective of the current study was to use the ACS combination regimens in vivo to demonstrate the molecular targets responsible for prevention of pancreatic cancer in N-nitrosobis(2-oxopropyl) amine (BOP) carcinogen treated Syrian golden hamsters. BOP treated Syrian golden hamsters (n=6/group) were sacrificed after 24 weeks of treatment with a low (20+45+1.6), medium (67+150+5) and high (200+450+16) doses (in mg/kg) of ACS, respectively. Saline and BOP controls were included in the study. The pancreatic tissues were processed for isolation of nuclear and cytoplasmic proteins, and 20 mg of tissue was used for isolation of total RNA. Results from the Western blot show that low dose of ACS combined regimen down-regulated active NF-κB by inhibiting phosphorylation of IαBβ and p65. Low dose ACS also inhibited phosphorylation of Akt, needed for IKK activation. Consequently at the transcription level, low dose ACS significant down-regulated NF-κB regulated gene products TNFα, IL1α and IL6 compared to BOP controls (p<0.05). Thus, low dose ACS inhibited the translocation of NF-κB into the nucleus by inhibiting the phosphorylation of IαBβ and p65. In addition, RT qPCR analysis of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cyclin D1 show >2 fold down-regulation in low dose regimen compared to BOP controls. With the high and medium doses, a trend similar to the low dose ACS was evident, whereby the effects were more significant at higher doses (p<0.001), thus demonstrating a dose-dependent response. The significance of this work is in the demonstration of the effectiveness in gene regulation of ACS even at the low-dose level which shows its potential as a powerful combinatorial regimen for pancreatic cancer prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2589. doi:1538-7445.AM2012-2589