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You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2012

219 DIFFERENTIAL EFFECT OF CALORIC AND CARBOHYDRATE RESTRICTION ON PROSTATE TUMOR CANCER GROWTH AND GENE EXPRESSION IN A XENOGRAFT MODEL

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    INTRODUCTION AND OBJECTIVES

    Caloric restriction (CR), under nutrition without malnourishment, has anti-cancer properties. We have shown carbohydrate restriction without CR slows prostate cancer (PC) growth. How the effects of carbohydrate restriction compare to CR is unknown. Moreover, whether the dietary make-up of a CR diet matters for PC growth is unclear. We examined the differential effects of caloric or carbohydrate restriction both separately and together upon PC growth in a xenograft model.

    METHODS

    124 ∼7 wk old male SCID mice were injected subcutaneously with 1x105 LAPC-4 PC cells. One week later, mice were randomized to 1 of 4 diets: ad libitum Western diet (no intervention, 44% carbs, 40% fat, and 16% protein), a No carbohydrate Ketogenic diet pair-fed to Western (NCKD; 1% carbs, 83% fat, 16% protein), Western diet calorically restricted (WCR), and NCKD calorically restricted (NCKD CR). CR arms were fed 75% of the calories of their reference diet. Tumor volumes and body weights were measured twice weekly. Mice were sacrificed when tumor volumes reached 1,000 mm3. Serum ELISA and tumor gene set expression analysis were performed.

    RESULTS

    By day 52, median tumor volumes for NCKD, WCR, and NCKD CR were 32%, 42%, and 62% smaller compared to Western (p≤0.001). There were no significant differences in terms of tumor volume among the intervention arms throughout the study. There was a suggestion that diet dictated survival (p=0.13). In 2-way comparisons, NCKD, NCKD CR, and WCR all had significantly prolonged survival vs, Western (all p≤0.02). However, no difference in survival was seen between any calorically or carbohydrate restricted arms (p>0.10). Carbohydrate- and caloric-restricted arms alike demonstrated relatively lower insulin, IGF-1, and IGFBP-3 levels relative to Western, with no difference amongst the 3 intervention arms. Tumor CXCR4 expression was significantly lower in the NCKD-based diet arms vs. Western.

    CONCLUSIONS

    Carbohydrate restriction and CR were equally effective at slowing PC growth and improving survival vs. a Western diet. Moreover, once CR is achieved, the dietary make-up has no further effect on PC growth. Beyond depressing the insulin/IGF-1 axis, known mitogens, NCKD-based diets lower tumor CXCR4 expression - a gene whose increased expression is associated with metastasis. Our findings lend further support for either carbohydrate restriction or CR in PC management, as well as demonstrating new evidence in how carbohydrate-restricted diets may influence PC progression.

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