New intervention studies in genetically obese mice employ a bean-based diet being tested for attenuation of colon carcinogenesis following exposure to azoxymethane. The bean-based diet was chosen to mimic conditions in the recently completed polyp prevention trial in which human subjects consuming the highest quartile of beans (navy, lima, kidney, black etc) showed a 3-fold reduction in ocurrence of advanced adenoma (E. Lanza and coworkers 2006, 2009). The whole beans and two bean fractions showed efficacy in attenuating tumor multiplicity (Bobe et al, Nutr Ca 2008). Recent studies have identified inflammation-associated cytokines including IL-6 as indicators of bean-diet efficacy (Mentor-Marcel et al Ca Prev Res 2009). Current studies are aimed at identifying funtionally significant molecular targets of the bean diets under conditions of efficacy as well as predictive biomarkers. Non-invasive gene expression profiling of fecal colonocytes has revealed sets of 2 to 3 genes whose changes are indicative of risk (Zhao et al Ca Prev Res 2009). In collaboration with the Small Animal Imaging facility at NCI Frederick we have demonstrated with magnetic resonance imaging that the endpoints of inflammation, tumor promotion and tumor progression can be monitored during colon carcinogenesis in a mouse model (Young et al Neoplasia 2009). These imageable markers are being used to compare the effects of short term exposure to dietary interventions in preclinical studies. Recently, in collaboration with Terry Hartman and coworkers (Penn State Univ) we have queried serum biomarkers for predictive value in short term controlled feeding intervention studies of men at risk of polyp recurrence in the Legume Intervention Feeding Experiment (LIFE) study. Serum levels of proinflammatory proteins decreased and serum lipid profiles improved in response to the bean-based diet (Hartman et al J Nutr 2010;Zhang Z et al Lipids 2010). The Obese mouse bean intervention study of biomarkers (Mentor-Marcel) turned out to agree with a recent analysis of the 4000 participant Polyp Prevention Trial samples. In both cases serum IL-6 levels were elevated in those at greatest risk of polyp recurrence (occurrence) and IL-6 levels were attenuated by the bean based diet in the complier group who benefited (Bobe et al Cancer Prev Res 2010).In the LIFE study the high legume low glycemic index diet reduces plasma leptin (Zhang et al, Eur J Clin Nutr 2011) as well as producing weight loss in overweight men. Interventions with berries (Mentor-Marcel et al Nutr Ca 2012) or the flavonoid isorhamnitin (Saud et al Cancer Res 2013) under conditions that prevent colon carcinogenesis in humans or mice revealed potentially predictive biomarkers. In addition emerged the surprising finding that isorhamnitin exerts its chemopreventive activity by targeting the endogenous inhibitor of oncogenic Src CSK. These findings are among the first to demonstrate biomarkers as well as pathways that can identify those likely to benefit from the dietary intervention with reduced colon polyp recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011159-05
Application #
8763373
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$191,925
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Saud, Shakir M; Li, Weidong; Gray, Zane et al. (2016) Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-κB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3β. Cancer Prev Res (Phila) 9:607-15
Li, Weidong; Hua, Baojin; Saud, Shakir M et al. (2015) Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Mol Carcinog 54:1096-109
Li, Weidong; Saud, Shakir M; Young, Matthew R et al. (2015) Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. Mol Cell Biochem 406:63-73
Saud, Shakir M; Young, Matthew R; Jones-Hall, Yava L et al. (2013) Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β-catenin. Cancer Res 73:5473-84
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Mentor-Marcel, Roycelynn A; Bobe, Gerd; Sardo, Christine et al. (2012) Plasma cytokines as potential response indicators to dietary freeze-dried black raspberries in colorectal cancer patients. Nutr Cancer 64:820-5
Zhang, Z; Lanza, E; Ross, A C et al. (2011) A high-legume low-glycemic index diet reduces fasting plasma leptin in middle-aged insulin-resistant and -sensitive men. Eur J Clin Nutr 65:415-8
Bobe, Gerd; Murphy, Gwen; Albert, Paul S et al. (2011) Do interleukin polymorphisms play a role in the prevention of colorectal adenoma recurrence by dietary flavonols? Eur J Cancer Prev 20:86-95
Zhang, Zhiying; Lanza, Elaine; Kris-Etherton, Penny M et al. (2010) A high legume low glycemic index diet improves serum lipid profiles in men. Lipids 45:765-75
Bobe, Gerd; Albert, Paul S; Sansbury, Leah B et al. (2010) Interleukin-6 as a potential indicator for prevention of high-risk adenoma recurrence by dietary flavonols in the polyp prevention trial. Cancer Prev Res (Phila) 3:764-75

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