Low-carbohydrate diets and prostate cancer: how low is "low enough"?

Abstract

Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet. As it is nearly impossible for humans to consume and maintain NCKD, we determined whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD. A total of 150 male severe combined immunodeficient mice were fed a Western diet ad libitum, injected with the human prostate cancer cell line LAPC-4, and then randomized 2 weeks later to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate diets. Ten mice not injected were fed an ad libitum low-fat diet (12% fat kcal) serving as the reference in a modified-paired feeding protocol. Mice were sacrificed when tumors reached 1,000 mm(3). Despite consuming extra calories, all mice receiving low-carbohydrate diets were significantly lighter than those receiving a low-fat diet (P < 0.04). Among the low-carbohydrate arms, NCKD-fed mice were significantly lighter than the 10% or 20% carbohydrate groups (P < 0.05). Tumors were significantly larger in the 10% carbohydrate group on days 52 and 59 (P < 0.05), but at no other point during the study. Diet did not affect survival (P = 0.34). There were no differences in serum insulin-like growth factor-I or insulin-like growth factor binding protein-3 at sacrifice among the low-carbohydrate arms (P = 0.07 and P = 0.55, respectively). Insulin was significantly lower in the 20% carbohydrate arm (P = 0.03). LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival as mice consuming NCKD (0% carbohydrate kcal).

Fig. 1

Mouse energy intake and body weights. A total of 150 severe combined immunodeficient mice (6-week-old males) were fed NCKD, 10% carbohydrate (Carb) diet, or 20% carbohydrate diet 2 weeks after injection with LAPC-4 tumor cells. An extra 10 mice not injected with tumor were fed a low-fat diet and used as the reference group in a modified paired-feeding protocol. A, energy intake 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 cages at the beginning of each feeding period. B, body weights of mice were measured three times per week. Each value represents the mean of each group (*, P < 0.05). The SEM is represented by error bars.

Fig. 2

Analysis of glucose and ketones. Box-plot representation of serum glucose (A) and urinary ketone (B) levels before randomization (day -3; top) and at sacrifice (bottom). Closed circles represent outliers.

Fig. 3

LAPC-4 xenograft tumor growth in severe combined immunodeficient 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 two times per week. A, values are expressed as the median of each group. Curves only extend to 65 days because after this time, >50% of the mice fed with the 10% carbohydrate diet had been sacrificed, and therefore the median tumor volume is not meaningful (*, P < 0.04, Kruskal-Wallis). The SEM is represented by error bars. B, box-plot representation of serum PSA levels at the time of sacrifice. Closed circles represent outliers.

Fig. 4

Kaplan-Meier survival plot of overall mouse survival by dietary group (P = 0.32).

Fig. 5

Analysis of the IGF axis. Box-plot representation of serum hormone levels within the IGF axis at the time of sacrifice. A, insulin. B, IGF-I. C, IGFBP-3. D, ratio between IGF-I and IGFBP-3. Closed circles represent outliers.