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Synergic chemoprevention with dietary carbohydrate restriction and supplementation of AMPK-activating phytochemicals: the role of SIRT1

 Jong Doo Lee  ;  Min-Ah Choi  ;  Simon Weonsang Ro  ;  Woo Ick Yang  ;  Arthur E.H. Cho  ;  Hye-Lim Ju  ;  Sinhwa Baek  ;  Sook In Chung  ;  Won Jun Kang  ;  Mijin Yun  ;  Jeon Han Park 
 European Journal of Cancer Prevention, Vol.25(1) : 54-64, 2016 
Journal Title
 European Journal of Cancer Prevention 
Issue Date
AMP-Activated Protein Kinases/metabolism* ; Animals ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Proliferation/drug effects ; Chromatin Immunoprecipitation ; Dietary Carbohydrates/administration & dosage* ; Dietary Carbohydrates/pharmacology ; Dietary Supplements* ; Drug Synergism ; Liver Neoplasms, Experimental/metabolism ; Liver Neoplasms, Experimental/mortality ; Liver Neoplasms, Experimental/pathology ; Liver Neoplasms, Experimental/prevention & control* ; Male ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/mortality ; Melanoma, Experimental/pathology ; Melanoma, Experimental/prevention & control* ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Oligonucleotide Array Sequence Analysis ; Phosphorylation ; Phytochemicals/administration & dosage* ; Phytochemicals/pharmacokinetics ; Signal Transduction ; Sirtuin 1/genetics ; Sirtuin 1/metabolism* ; Survival Rate ; Tumor Cells, Cultured
AMPK ; carbohydrate restriction ; chemoprevention ; energy metabolism ; liver cancer ; melanoma ; phytochemical ; 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.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Liver Cirrhosis Clinical Research Center (간경변증임상연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
강원준(Kang, Won Jun) ORCID logo https://orcid.org/0000-0002-2107-8160
노원상(Ro, Simon Weonsang) ORCID logo https://orcid.org/0000-0003-2187-3698
박전한(Park, Jeon Han) ORCID logo https://orcid.org/0000-0001-9604-3205
양우익(Yang, Woo Ick) ORCID logo https://orcid.org/0000-0002-6084-5019
윤미진(Yun, Mi Jin) ORCID logo https://orcid.org/0000-0002-1712-163X
이종두(Lee, Jong Doo)
정숙인(Chung, Sook In) ORCID logo https://orcid.org/0000-0002-7915-9203
조응혁(Cho, Arthur Eung Hyuck) ORCID logo https://orcid.org/0000-0001-8670-2473
최민아(Choi, Min Ah)
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