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Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveals the potential role of ketogenesis to slow tumor growth: a secondary analysis of the CAPS2 diet trial.

Publication ,  Journal Article
Chi, J-T; Lin, P-H; Tolstikov, V; Howard, L; Chen, EY; Bussberg, V; Greenwood, B; Narain, NR; Kiebish, MA; Freedland, SJ
Published in: Prostate Cancer Prostatic Dis
April 2022

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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Published In

Prostate Cancer Prostatic Dis

DOI

EISSN

1476-5608

Publication Date

April 2022

Volume

25

Issue

4

Start / End Page

770 / 777

Location

England

Related Subject Headings

  • Urology & Nephrology
  • Prostatic Neoplasms
  • Prostate-Specific Antigen
  • Prostate
  • Male
  • Ketone Bodies
  • Humans
  • Diet, Carbohydrate-Restricted
  • Carbohydrates
  • 3211 Oncology and carcinogenesis
 

Citation

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Chi, J.-T., Lin, P.-H., Tolstikov, V., Howard, L., Chen, E. Y., Bussberg, V., … Freedland, S. J. (2022). Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveals the potential role of ketogenesis to slow tumor growth: a secondary analysis of the CAPS2 diet trial. Prostate Cancer Prostatic Dis, 25(4), 770–777. https://doi.org/10.1038/s41391-022-00525-6
Chi, Jen-Tsan, Pao-Hwa Lin, Vladimir Tolstikov, Lauren Howard, Emily Y. Chen, Valerie Bussberg, Bennett Greenwood, Niven R. Narain, Michael A. Kiebish, and Stephen J. Freedland. “Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveals the potential role of ketogenesis to slow tumor growth: a secondary analysis of the CAPS2 diet trial.Prostate Cancer Prostatic Dis 25, no. 4 (April 2022): 770–77. https://doi.org/10.1038/s41391-022-00525-6.
Chi J-T, Lin P-H, Tolstikov V, Howard L, Chen EY, Bussberg V, Greenwood B, Narain NR, Kiebish MA, Freedland SJ. Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveals the potential role of ketogenesis to slow tumor growth: a secondary analysis of the CAPS2 diet trial. Prostate Cancer Prostatic Dis. 2022 Apr;25(4):770–777.

Published In

Prostate Cancer Prostatic Dis

DOI

EISSN

1476-5608

Publication Date

April 2022

Volume

25

Issue

4

Start / End Page

770 / 777

Location

England

Related Subject Headings

  • Urology & Nephrology
  • Prostatic Neoplasms
  • Prostate-Specific Antigen
  • Prostate
  • Male
  • Ketone Bodies
  • Humans
  • Diet, Carbohydrate-Restricted
  • Carbohydrates
  • 3211 Oncology and carcinogenesis