224 Synergic tumor growth suppression with carbohydrate-restriction diet and natural AMP-dependent protein kinase activators

Abstract

Background: Calorie restriction (CR) or low-carbohydrate diet (LCD) can increase life-span in normal cells but inhibit carcinogenesis. Various AMPdependent protein kinase (AMPK) activating phytochemicals also have CR-mimetic anticancer properties. We investigated whether carbohydraterestriction diet and phytochemical supplementation induce synergic tumor suppression. Methods: We used a mixture of curcumin, quercetin, catechins and resveratrol extracts for natural AMPK-activating agent. Survival analysis was performed in B16F10 melanoma model after fed control diet, control diet with phytochemicals (MP formula), LCD, LCD with phytochemicals (LCDmp), moderate-carbohydrate diet (MCD), and MCD with phytochemicals (MCDmp). Tumor suppression mechanisms, especially alterations in energy-dependent signaling pathways, histone methylation, and global gene expression were investigated. We evaluated the role of SIRT1 under glucose-restriction condition with MTT assay. Diet-induced cancer prevention effects were analyzed in a transgenic liver cancer model. Results: In melanoma model, MP, LCD, or MCD intervention did not produce survival benefit but LCDmp and MCDmp interventions increased median survival time significantly (p < 0.05). Suppression of the IGF-1R/PI3K/Akt/mTOR signaling, activation of the AMPK/SIRT1/LKB1pathway and NF-kB suppression were the major tumor suppression mechanisms. MTT assay showed suppressed proliferation of the B16F10 and A375SM cells after treatment of SIRT1 activator under low-glucose condition. Alterations in histone methylation within Pten and FoxO3a were demonstrated in tumor tissues. In transgenic liver cancer model, the MCDmp and LCDmp groups showed fewer tumor nodules. Microarray analysis revealed increased PPARa with decreased IL-6 and NF-kB after MCDmp intervention, which could be the major cancer prevention mechanism. Conclusion: AMPK-activating phytochemicals exert synergic anti-cancer activities under low-carbohydrate condition, and SIRT1 induces tumor suppression.