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Int J Mol Sci ; 19(2)2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29439410


Intravenous administration of high-dose ascorbic acid (AA) has been reported as a treatment for cancer patients. However, cancer patients with renal failure cannot receive this therapy because high-dose AA infusion can have side effects. To solve this problem, we evaluated the antitumor activity of a lipophilic stable AA derivative, 2-O-α-d-glucopyranosyl-6-O-(2-pentylheptanoyl)-l-ascorbic acid (6-bOcta-AA-2G). Intravenous administration of 6-bOcta-AA-2G suppressed tumor growth in colon-26 tumor-bearing mice more strongly than did AA, even at 1/10 of the molar amount of AA. Experiments on the biodistribution and clearance of 6-bOcta-AA-2G and its metabolites in tumor-bearing mice showed that 6-bOcta-AA-2G was hydrolyzed to 6-O-(2-propylpentanoyl)-l-ascorbic acid (6-bOcta-AA) slowly to yield AA, and the results suggested that this characteristic metabolic pattern is responsible for making the antitumor activity of 6-bOcta-AA-2G stronger than that of AA and that the active form of 6-bOcta-AA-2G showing antitumor activity is 6-bOcta-AA. In in vitro experiments, the oxidized form of 6-bOcta-AA as well as 6-bOcta-AA showed significant cytotoxicity, while the oxidized forms of ascorbic acid showed no cytotoxicity at all, suggesting that the antitumor activity mechanism of 6-bOcta-AA-2G is different from that of AA and that the antitumor activity is due to the reduced and oxidized form of 6-bOcta-AA. The findings suggest that 6-bOcta-AA-2G is a potent candidate as an alternative drug to intravenous high-dose AA.

Antineoplásicos/uso terapêutico , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/uso terapêutico , Glucosídeos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Ácido Ascórbico/síntese química , Ácido Ascórbico/farmacocinética , Linhagem Celular Tumoral , Feminino , Glucosídeos/síntese química , Glucosídeos/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Tecidual
Biochem Biophys Res Commun ; 486(2): 476-480, 2017 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-28315682


Both cholesterol and α-tocopherol are essential lipophilic nutrients for humans and animals. Although cholesterol in excess causes severe problems such as coronary heart disease, it is a necessary component of cell membranes and is the precursor for the biosynthesis of steroid hormones and bile acids. Niemann-Pick C1-like 1 (NPC1L1) is a cholesterol transporter that is highly expressed in the small intestine and liver in humans and plays an important role in cholesterol homeostasis. Cholesterol promotes NPC1L1 endocytosis, which is an early step in cholesterol uptake. Furthermore, α-tocopherol is the most active form of vitamin E, and sufficient amounts of vitamin E are critical for health. It has been reported that NPC1L1 mediates α-tocopherol absorption; however, the mechanisms underlying this process are unknown. In this study, we found that treatment of cells that stably express NPC1L1-GFP with α-tocopherol promotes NPC1L1 endocytosis, and the NPC1L1 inhibitor, ezetimibe, efficiently prevents the α-tocopherol-induced endocytosis of NPC1L1. Cholesterol binding to the N-terminal domain (NTD) of NPC1L1 (NPC1L1-NTD) is essential for NPC1L1-mediated cholesterol absorption. We found that α-tocopherol competitively binds NPC1L1-NTD with cholesterol. Furthermore, when cells stably expressed NPC1L1ΔNTD-GFP, α-tocopherol could not induce the endocytosis of NPC1L1ΔNTD. Taken together, these results demonstrate that NPC1L1 recognizes α-tocopherol via its NTD and mediates α-tocopherol uptake through the same mechanism as cholesterol absorption.

Colesterol/metabolismo , Hepatócitos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , alfa-Tocoferol/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Ligação Competitiva , Transporte Biológico , Células CACO-2 , Linhagem Celular Tumoral , Colesterol/farmacologia , Endocitose/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Ezetimiba/farmacologia , Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Plasmídeos/química , Plasmídeos/metabolismo , Ligação Proteica , Domínios Proteicos , Ratos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética