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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

Abstract

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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Fig. 1: Top serum metabolites and metabolic pathways altered at 3- and 6-month in participants receiving LCD.
Fig. 2: The metabolites which were significantly elevated by LCD.
Fig. 3: The metabolites which were significantly reduced by LCD.
Fig. 4: The metabolites whose LCD-changed positively correlated with PSADT.
Fig. 5: The metabolites whose LCD-changed negatively correlated with PSADT.

Data availability

The metabolomic data will be made available to the academic community upon publication of the manuscript.

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Acknowledgements

American Urological Association Foundation, BERG, NIH, and Robert C. and Veronica Atkins Foundation.

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JTC: data analysis, manuscript writing—original draft, review and editing. PHL: Conceptualization, data analysis, manuscript writing. VT, VB, NRN, BG, RS: methodology, data acquisition, statistical analysis. TO: statistical analysis. EC: methodology, project, administration, data acquisition, statistical analysis. CGA and AR: manuscript writing. MAK: Conceptualization, methodology, project administration, data acquisition, statistical analysis. SJF: Conceptualization, funding acquisitions, manuscript writing.

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Correspondence to Jen-Tsan Chi or Stephen J. Freedland.

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Chi, JT., Lin, PH., Tolstikov, V. et al. 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). https://doi.org/10.1038/s41391-022-00525-6

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