Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer.
Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer.
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DOI：
10.1111/j.1464-410x.2012.10971.x
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发表时间：
2012-10
影响因子：
4.5
通讯作者：
Freedland SJ
中科院分区：
文献类型：
--
作者：
Kim HS;Masko EM;Poulton SL;Kennedy KM;Pizzo SV;Dewhirst MW;Freedland SJ
确定无碳水化合物生酮饮食（NCKD）和乳酸转运蛋白抑制剂是否可在人前列腺癌异种移植小鼠模型中对延迟前列腺肿瘤生长发挥协同作用。将120只裸无胸腺雄性小鼠（6-8周龄）皮下注射至小鼠皮下。在侧腹中具有1.0 × 105个LAPC-4前列腺癌细胞。将小鼠随机分配至4个处理组之一：西方饮食（WD，35%脂肪，16%蛋白质，49%碳水化合物）和溶媒（Veh）处理;通过微型渗透泵递送α-氰基-4-羟基肉桂酸酯（CHC）抑制WD和单羧酸转运蛋白-1（MCT 1）; NCKD（84%脂肪，16%蛋白质，0%碳水化合物）加Veh ;或NCKD和MCT 1抑制。每周三次喂食小鼠并称重，并调整饲料以维持相似的体重。每周两次测量肿瘤大小，并通过所有四组的Kruskal -沃利斯分析来测试治疗的组合效果。使用线性回归分析检验了治疗（NCKD vs. WD和CHC vs. Veh）对肿瘤体积的独立影响。所有小鼠在第53天（泵排出结束）处死，并分析血清和肿瘤切片的各种标志物。同样，分别使用Kruskal -沃利斯和线性回归分析检验了给药的组合和独立效应。四组之间的肿瘤体积无显著差异（P=0.09）。当测试治疗的独立效果时，NCKD与实验结束时的较低肿瘤体积显著相关（P=0.026），而CHC施用则不相关（P=0.981）。然而，CHC与坏死分数增加相关（P<0.001）。仅在喂食NCKD的小鼠和喂食WD的小鼠之间的比较中观察到肿瘤体积的差异。MCT 1抑制对肿瘤体积没有显著影响，尽管它与坏死分数增加相关。
To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer. 120 nude athymic male mice (aged 6–8 weeks) were injected s.c. in the flank with 1.0 x 105 LAPC-4 prostate cancer cells. Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4-hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh ; or NCKD and MCT1 inhibition. Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal – Wallis analysis of all four groups. Independent effects of treatment (NCKD vs. WD and CHC vs. Veh) on tumour volume were tested using linear regression analysis. All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal – Wallis and linear regression analysis, respectively. There were no significant differences in tumour volumes among the four groups (P=0.09). When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P=0.026), while CHC administration was not (P=0.981). However, CHC was associated with increased necrotic fraction (P<0.001). Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction.