Abstract 2970: Differential effects of caloric and carbohydrate restriction on prostate cancer in a mouse model
Authors: Macias Everardo , Thomas Jean A. , Masko Elizabeth M. , Gaines Alexis R. , Whitley Brian , Coburn Tanisha , Poulton Susan L. , Phillips Tameika E. , Freedland Stephen J. 
Published: May 2015

Abstract
Prostate cancer (PC) is the most common non-cutaneous malignancy in men in the United States. Animal studies have shown that dietary interventions, specifically dietary restriction, demonstrate an ability to inhibit prostate tumor growth and progression. Classically, dietary restriction has come in the form of global caloric restriction (CR). CR, without malnutrition, has been consistently shown to be effective in reducing age-related conditions as well as decreasing the spontaneous incidence and progression of multiple cancers. In contrast to the generalized reduction of calories seen in CR, an alternative manner of dietary restriction would be to restrict specific macronutrients. In prior studies, we have tested the theory that specifically restricting carbohydrates could slow tumor growth by providing mice a diet deplete of carbohydrates (i.e. a no-carbohydrate Ketogenic diet or NCKD). As such, we previously found that in a prostate cancer xenograft study, mice fed a NCKD, in the presence or absence of weight loss, had improved mouse survival as well as slowed tumor growth with respect to a diet complete of carbohydrates (i.e. Western diet). Moreover, NCKD, like CR, appeared to inhibit tumor growth via depression of the insulin/IGF-1 axis. These series of studies suggest that CR and NCKD may act via overlapping molecular mechanisms that inhibit tumor growth, however, no study to date has directly compared the effects of carbohydrate versus caloric restriction. Therefore we sought to investigate the role of global CR and NCKD without CR on tumor growth side by side. In addition, we sought to determine whether calorie restriction of NCKD would provide an additional inhibitory effect (i.e. CR + NCDK). This study consisted of four arms: 1) Western Diet (WD); 2) NCKD (pair fed with WD); 3) western diet 25% calorie restricted (WD-CR) and 4) NCKD 25% CR (NCKD-CR). By day 52 after randomization, when median tumor volumes for WD mice were ∼1000 mm3, NCKD, Western CR and NCKD CR arms had 32.2%, 41.6%, and 62.1% smaller tumor volumes, respectively, relative to WD mice (all p&lt;0.01). At sacrifice, both calorically restricted groups had significantly lower serum glucose levels than the non-calorically restricted arms. Moreover, IGF-1:IGFBP-3 levels of all active experimental arms (NCKD, WD-CR, and NCKD-CR) were significantly lower than WD mice. Among the two CR arms, IGF-1: IGFBP-3 ratios were lower in the NCKD-CR mice. These data suggest that CR and NCKD have similar efficacy in reducing tumor growth and both act, at least in part, via reductions in IGF-1. Also, the combination of CR plus NCKD had an additive effect. Global gene expression analysis of xenograft tumors revealed genes altered in a similar fashion across the three diets in comparison to WD, but also genes uniquely altered in individual diets. Further analysis of these genes will allow us to better understand the molecular mechanisms through which these dietary regimens inhibit tumor growth.
Citation Format: Everardo Macias, Jean A. Thomas, Elizabeth M. Masko, Alexis R. Gaines, Brian Whitley, Tanisha Coburn, Susan L. Poulton, Tameika E. Phillips, Stephen J. Freedland. Differential effects of caloric and carbohydrate restriction on prostate cancer in a mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2970. doi:10.1158/1538-7445.AM2014-2970