Synergic chemoprevention with dietary carbohydrate restriction and supplementation of AMPK-activating phytochemicals: the role of SIRT1.
Calorie restriction or a low-carbohydrate diet (LCD) can increase life span in normal cells while inhibiting carcinogenesis. Various phytochemicals also have calorie restriction-mimetic anticancer properties. We investigated whether an isocaloric carbohydrate-restriction diet and AMP-activated protein kinase (AMPK)-activating phytochemicals induce synergic tumor suppression. We used a mixture of AMPK-activating phytochemical extracts including curcumin, quercetin, catechins, and resveratrol. Survival analysis was carried out in a B16F10 melanoma model fed a control diet (62.14% kcal carbohydrate, 24.65% kcal protein and 13.2% kcal fat), a control diet with multiple phytochemicals (MP), LCD (16.5, 55.2, and 28.3% kcal, respectively), LCD with multiple phytochemicals (LCDmp), a moderate-carbohydrate diet (MCD, 31.9, 62.4, and 5.7% kcal, respectively), or MCD with phytochemicals (MCDmp). Compared with the control group, MP, LCD, or MCD intervention did not produce survival benefit, but LCDmp (22.80±1.58 vs. 28.00±1.64 days, P=0.040) and MCDmp (23.80±1.08 vs. 30.13±2.29 days, P=0.008) increased the median survival time significantly. Suppression of the IGF-1R/PI3K/Akt/mTOR signaling, activation of the AMPK/SIRT1/LKB1pathway, and NF-κB suppression were the critical tumor-suppression mechanisms. In addition, SIRT1 suppressed proliferation of the B16F10 and A375SM cells under a low-glucose condition. Alterations in histone methylation within Pten and FoxO3a were observed after the MCDmp intervention. In the transgenic liver cancer model developed by hydrodynamic transfection of the HrasG12V and shp53, MCDmp and LCDmp interventions induced significant cancer-prevention effects. Microarray analysis showed that PPARα increased with decreased IL-6 and NF-κB within the hepatocytes after an MCDmp intervention. In conclusion, an isocaloric carbohydrate-restriction diet and natural AMPK-activating agents induce synergistic anticancer effects. SIRT1 acts as a tumor suppressor under a low-glucose condition.
aSeverance Biomedical Science Institute bDepartment of Nuclear Medicine cDepartment of Internal Medicine dLiver Cirrhosis Clinical Research Center eDepartment of Pathology fBrain Korea 21 PLUS for Medical Science gDepartment of Microbiology hYonsei Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Jong Doo
JD
Lee
Min-Ah
MA
Choi
Simon Weonsang
SW
Ro
Woo Ick
WI
Yang
Arthur E H
AE
Cho
Hye-Lim
HL
Ju
Sinhwa
S
Baek
Sook In
SI
Chung
Won Jun
WJ
Kang
Mijin
M
Yun
Jeon Han
JH
Park
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004040:Dietary Carbohydrates / Q000008:administration & dosage* / Q000494:pharmacology; D019587:Dietary Supplements; D004357:Drug Synergism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D064209:Phytochemicals / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D004040:Dietary Carbohydrates; D064209:Phytochemicals; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1