Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis

Abstract

Background: Recent evidence suggests carbohydrate intake may influence prostate cancer biology. We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model.

Methods: Seventy-five male SCID mice were fed a NCKD (84% fat-0% carbohydrate-16% protein kcal), low-fat (12% fat-72% carbohydrate-16% protein kcal), or Western diet (40% fat-44% carbohydrate-16% protein kcal). Low-fat mice were fed ad libitum and the other arms fed via a modified-paired feeding protocol. After 24 days, all mice were injected with LAPC-4 cells and sacrificed when tumors approached 1,000 mm(3).

Results: Despite consuming equal calories, NCKD-fed mice lost weight (up to 15% body weight) relative to low-fat and Western diet-fed mice and required additional kcal to equalize body weight. Fifty-one days after injection, NCKD mice tumor volumes were 33% smaller than Western mice (rank-sum, P = 0.009). There were no differences in tumor volume between low-fat and NCKD mice. Dietary treatment was significantly associated with survival (log-rank, P = 0.006), with the longest survival among the NCKD mice, followed by the low-fat mice. Serum IGFBP-3 was highest and IGF-1:IGFBP-3 ratio was lowest among NCKD mice while serum insulin and IGF-1 levels were highest in Western mice. NCKD mice had significantly decreased hepatic fatty infiltration relative to the other arms.

Conclusions: In this xenograft model, despite consuming more calories, NCKD-fed mice had significantly reduced tumor growth and prolonged survival relative to Western mice and was associated with favorable changes in serum insulin and IGF axis hormones relative to low-fat or Western diet.

(c) 2007 Wiley-Liss, Inc.

Figures

Fig. 1

Mouse energy in take and body weights. Seventy-five 3–4-week-old male SCID mice were fed either a NCKD, low-fat, or Western diet for 24 days and then injected subcutaneously in the flank with 1 × 105 LAPC-4 tumor cells in 0.1 ml of Matrigel. A: Energy in take was measured for each mouse three times per week by subtracting the weight of uneaten food from the weight of the food placed into the feeding receptacles at the beginning of each feeding period. B: Mice were weighed three times per week from the start of the experiment. Values are mean of each group. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 2

Box-plot expression of (A) serum glucose and (B) urinary ketone levels measured at day −2 and again at day 35. Box represents 25th and 75th percentile expression and bar represents median. Whiskers correspond to 5th and 95th percentile and outliers are marked separately.

Fig. 3

LAPC-4 xenograft tumor growth in SCID mice. Mice were injected subcutaneously in the flank with 1 × 105 LAPC-4 tumor cells in 0.1 ml of Matrigel. Once the tumors became palpable, tumor volume was measured three times per week. Values are expressed as median of each group. Curves only extend to 60 days because after 60 days, >50% of the Western diet mice had been sacrificed and therefore median tumor volume is not meaningful. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 4

Kaplan–Meier survival plot of overall mouse survival by dietary group. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 5

Box-plot expression of serum hormone concentrations or fatty liver infiltration at the time of sacrifice across the dietary groups. A: Serum insulin. B: Serum IGF-1. C: Serum IGFBP-3. D: The ratio of serum IGF-1:IGFBP-3. E: Fatty liver in filtration as scored by two independent pathologists with the average of the 2 scores from the pathologists presented. Box represents 25th and 75th percentile expression and bar represents median. Whiskers correspond to 5th and 95th percentile and outliers are marked separately.