The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model.
OBJECTIVE
Numerous dietary factors elevate serum levels of insulin and insulin-like growth factor I (IGF-I), both potent prostate cancer mitogens. We tested whether varying dietary carbohydrate and fat, without energy restriction relative to comparison diets, would slow tumor growth and reduce serum insulin, IGF-I, and other molecular mediators of prostate cancer in a xenograft model.


METHODS
Individually caged male severe combined immunodeficient mice (n = 130) were randomly assigned to one of three diets (described as percent total calories): very high-fat/no-carbohydrate ketogenic diet (NCKD: 83% fat, 0% carbohydrate, 17% protein), low-fat/high-carbohydrate diet (LFD: 12% fat, 71% carbohydrate, 17% protein), or high-fat/moderate-carbohydrate diet (MCD: 40% fat, 43% carbohydrate, 17% protein). Mice were fed to maintain similar average body weights among groups. Following a preliminary feeding period, mice were injected with 1 x 10(6) LNCaP cells (day 0) and sacrificed when tumors were >or=1,000 mm(3).


RESULTS
Two days before tumor injection, median NCKD body weight was 2.4 g (10%) and 2.1 g (8%) greater than the LFD and MCD groups, respectively (P < 0.0001). Diet was significantly associated with overall survival (log-rank P = 0.004). Relative to MCD, survival was significantly prolonged for the LFD (hazard ratio, 0.49; 95% confidence interval, 0.29-0.79; P = 0.004) and NCKD groups (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.02). Median serum insulin, IGF-I, IGF-I/IGF binding protein-1 ratio, and IGF-I/IGF binding protein-3 ratio were significantly reduced in NCKD relative to MCD mice. Phospho-AKT/total AKT ratio and pathways associated with antiapoptosis, inflammation, insulin resistance, and obesity were also significantly reduced in NCKD relative to MCD tumors.


CONCLUSIONS
These results support further preclinical exploration of carbohydrate restriction in prostate cancer and possibly warrant pilot or feasibility testing in humans.
Mavropoulos
John C
JC
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Buschemeyer
W Cooper
WC
Tewari
Alok K
AK
Rokhfeld
Dmitriy
D
Pollak
Michael
M
Zhao
Yunhua
Y
Febbo
Phillip G
PG
Cohen
Pinchas
P
Hwang
David
D
Devi
Gayathri
G
Demark-Wahnefried
Wendy
W
Westman
Eric C
EC
Peterson
Bercedis L
BL
Pizzo
Salvatore V
SV
Freedland
Stephen J
SJ
D000230:Adenocarcinoma / Q000097:blood / Q000178:diet therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D045744:Cell Line, Tumor / Q000637:transplantation; D050528:Diet, Carbohydrate-Restricted; D055423:Diet, Ketogenic; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000633:toxicity*; D004041:Dietary Fats / Q000008:administration & dosage / Q000627:therapeutic use*; D018450:Disease Progression; D005234:Fatty Liver / Q000209:etiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007659:Ketones / Q000652:urine; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000097:blood / Q000178:diet therapy* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000097:blood; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
D001786:Blood Glucose; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D007659:Ketones; D007334:Insulin-Like Growth Factor I; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt