The influence of low-carbohydrate diets on the metabolic response to androgen-deprivation therapy in prostate cancer
Corresponding Author
Jen-Tsan Chi MD, PhD
Department of Molecular Genetics and Microbiology, Center for Genomics and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA
Correspondence Jen-Tsan Chi, 101 Science Dr, DUMC 3382, CIEMAS 2177A, Durham, NC 27708, USA.
Email [email protected]
Stephen J. Freedland, W. Third St., Suite 1070W, Los Angeles, CA 90048, USA.
Email [email protected]
Search for more papers by this authorPao-Hwa Lin PhD
Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
Search for more papers by this authorTaofik Oyekunle MS
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
Search for more papers by this authorGloria C. Galvan PhD
Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, California, USA
Search for more papers by this authorAdela Ramirez-Torres PhD
Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, California, USA
Search for more papers by this authorBo Chi
Department of Molecular Genetics and Microbiology, Center for Genomics and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA
Search for more papers by this authorRangaprasad Sarangarajan B Pharm, PhD
BERG, Framingham, Massachusetts, USA
Search for more papers by this authorCorresponding Author
Stephen J. Freedland MD
Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, California, USA
Durham VA Medical Center, Durham, North Carolina, USA
Correspondence Jen-Tsan Chi, 101 Science Dr, DUMC 3382, CIEMAS 2177A, Durham, NC 27708, USA.
Email [email protected]
Stephen J. Freedland, W. Third St., Suite 1070W, Los Angeles, CA 90048, USA.
Email [email protected]
Search for more papers by this authorCorresponding Author
Jen-Tsan Chi MD, PhD
Department of Molecular Genetics and Microbiology, Center for Genomics and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA
Correspondence Jen-Tsan Chi, 101 Science Dr, DUMC 3382, CIEMAS 2177A, Durham, NC 27708, USA.
Email [email protected]
Stephen J. Freedland, W. Third St., Suite 1070W, Los Angeles, CA 90048, USA.
Email [email protected]
Search for more papers by this authorPao-Hwa Lin PhD
Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
Search for more papers by this authorTaofik Oyekunle MS
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
Search for more papers by this authorGloria C. Galvan PhD
Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, California, USA
Search for more papers by this authorAdela Ramirez-Torres PhD
Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, California, USA
Search for more papers by this authorBo Chi
Department of Molecular Genetics and Microbiology, Center for Genomics and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA
Search for more papers by this authorRangaprasad Sarangarajan B Pharm, PhD
BERG, Framingham, Massachusetts, USA
Search for more papers by this authorCorresponding Author
Stephen J. Freedland MD
Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, California, USA
Durham VA Medical Center, Durham, North Carolina, USA
Correspondence Jen-Tsan Chi, 101 Science Dr, DUMC 3382, CIEMAS 2177A, Durham, NC 27708, USA.
Email [email protected]
Stephen J. Freedland, W. Third St., Suite 1070W, Los Angeles, CA 90048, USA.
Email [email protected]
Search for more papers by this authorAbstract
Background
Prostate cancer (PC) is the second most lethal cancer for men. For metastatic PC, standard first-line treatment is androgen deprivation therapy (ADT). While effective, ADT has many metabolic side effects. Previously, we found in serum metabolome analysis that ADT reduced androsterone sulfate, 3-hydroxybutyric acid, acyl-carnitines but increased serum glucose. Since ADT reduced ketogenesis, we speculate that low-carbohydrate diets (LCD) may reverse many ADT-induced metabolic abnormalities in animals and humans.
Methods
In a multicenter trial of patients with PC initiating ADT randomized to no diet change (control) or LCD, we previously showed that LCD intervention led to significant weight loss, reduced fat mass, improved insulin resistance, and lipid profiles. To determine whether and how LCD affects ADT-induced metabolic changes, we analyzed serum metabolites after 3-, and 6-months of ADT on LCD versus control.
Results
We found androsterone sulfate was most consistently reduced by ADT and was slightly further reduced in the LCD arm. Contrastingly, LCD intervention increased 3-hydroxybutyric acid and various acyl-carnitines, counteracting their reduction during ADT. LCD also reversed the ADT-reduced lactic acid, alanine, and S-adenosyl methionine (SAM), elevating glycolysis metabolites and alanine. While the degree of androsterone reduction by ADT was strongly correlated with glucose and indole-3-carboxaldehyde, LCD disrupted such correlations.
Conclusions
Together, LCD intervention significantly reversed many ADT-induced metabolic changes while slightly enhancing androgen reduction. Future research is needed to confirm these findings and determine whether LCD can mitigate ADT-linked comorbidities and possibly delaying disease progression by further lowering androgens.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Open Research
DATA AVAILABILITY STATEMENT
The metabolomic data will be available upon requests after the publication of the manuscript.
Supporting Information
| Filename | Description |
|---|---|
| pros24136-sup-0001-Slide1.TIF756.7 KB | Supporting information. |
| pros24136-sup-0002-Fig_S2.tif1.4 MB | Supporting information. |
| pros24136-sup-0003-Fig_S3A.tif1.4 MB | Supporting information. |
| pros24136-sup-0004-Fig_S3B.tif1.3 MB | Supporting information. |
| pros24136-sup-0005-Fig_S3C.tif1.3 MB | Supporting information. |
| pros24136-sup-0006-Fig_S4A.tif1.3 MB | Supporting information. |
| pros24136-sup-0007-Fig_S4B.tif1.4 MB | Supporting information. |
| pros24136-sup-0008-BLvsM3volcanotable_TableS1.docx14.1 KB | Supporting information. |
| pros24136-sup-0009-BLvsM6volcanotable_TableS2.docx7.7 KB | Supporting information. |
| pros24136-sup-0010-LowCarb_ANDROSTERONE_SULFATE_BLto3Mand6M_Ranked_TableS3.docx29.7 KB | Supporting information. |
| pros24136-sup-0011-SupMat.docx13.2 KB | Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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