Department of Molecular Genetics and Microbiology, Center for Genomics and Computational Biology, Durham, NC, USA.
Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, NC, USA.
Prostate Cancer Prostatic Dis. 2022 Apr;25(4):770-777. doi: 10.1038/s41391-022-00525-6. Epub 2022 Mar 25.
Systemic treatments for prostate cancer (PC) have significant side effects. Thus, newer alternatives with fewer side effects are urgently needed. Animal and human studies suggest the therapeutic potential of low carbohydrate diet (LCD) for PC. To test this possibility, Carbohydrate and Prostate Study 2 (CAPS2) trial was conducted in PC patients with biochemical recurrence (BCR) after local treatment to determine the effect of a 6-month LCD intervention vs. usual care control on PC growth as measured by PSA doubling time (PSADT). We previously reported the LCD intervention led to significant weight loss, higher HDL, and lower triglycerides and HbA1c with a suggested longer PSADT. However, the metabolic basis of these effects are unknown.
To identify the potential metabolic basis of effects of LCD on PSADT, serum metabolomic analysis was performed using baseline, month 3, and month 6 banked sera to identify the metabolites significantly altered by LCD and that correlated with varying PSADT.
LCD increased the serum levels of ketone bodies, glycine and hydroxyisocaproic acid. Reciprocally, LCD reduced the serum levels of alanine, cytidine, asymmetric dimethylarginine (ADMA) and 2-oxobutanoate. As high ADMA level is shown to inhibit nitric oxide (NO) signaling and contribute to various cardiovascular diseases, the ADMA repression under LCD may contribute to the LCD-associated health benefit. Regression analysis of the PSADT revealed a correlation between longer PSADT with higher level of 2-hydroxybutyric acids, ketone bodies, citrate and malate. Longer PSADT was also associated with LCD reduced nicotinamide, fructose-1, 6-biphosphate (FBP) and 2-oxobutanoate.
These results suggest a potential association of ketogenesis and TCA metabolites with slower PC growth and conversely glycolysis with faster PC growth. The link of high ketone bodies with longer PSADT supports future studies of ketogenic diets to slow PC growth.
前列腺癌（PC）的系统治疗有显著的副作用。因此，迫切需要新的副作用更少的替代方法。动物和人体研究表明低碳水化合物饮食（LCD）对 PC 有治疗潜力。为了验证这一可能性，对局部治疗后出现生化复发（BCR）的 PC 患者进行了 Carbohydrate and Prostate Study 2（CAPS2）试验，以确定 6 个月的 LCD 干预与常规护理对照相比对 PC 生长的影响，PC 生长通过 PSA 倍增时间（PSADT）来衡量。我们之前报道过，LCD 干预导致体重显著减轻、高密度脂蛋白（HDL）升高、甘油三酯和糖化血红蛋白（HbA1c）降低，PSADT 延长。然而，这些影响的代谢基础尚不清楚。
为了确定 LCD 对 PSADT 影响的潜在代谢基础，使用基线、第 3 个月和第 6 个月的储存血清进行血清代谢组学分析，以确定被 LCD 显著改变且与 PSADT 变化相关的代谢物。
LCD 增加了血清酮体、甘氨酸和羟基异己酸的水平。相反，LCD 降低了血清丙氨酸、胞苷、不对称二甲基精氨酸（ADMA）和 2-氧代丁酸的水平。由于高水平的 ADMA 被证明抑制一氧化氮（NO）信号并导致各种心血管疾病，因此在 LCD 下 ADMA 的抑制可能有助于与 LCD 相关的健康益处。PSADT 的回归分析显示，较长的 PSADT 与较高水平的 2-羟基丁酸、酮体、柠檬酸和苹果酸相关。较长的 PSADT 还与 LCD 降低烟酰胺、果糖-1,6-二磷酸（FBP）和 2-氧代丁酸有关。
这些结果表明酮生成和 TCA 代谢物与 PC 生长较慢之间存在潜在关联，相反，糖酵解与 PC 生长较快之间存在关联。较高的酮体与较长的 PSADT 之间的联系支持未来研究酮饮食以减缓 PC 生长。
