Allicin, a Potent New Ornithine Decarboxylase Inhibitor in Neuroblastoma Cells.,Journal of Natural Products

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Allicin, a Potent New Ornithine Decarboxylase Inhibitor in Neuroblastoma Cells.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-08-12 , DOI: 10.1021/acs.jnatprod.0c00613
Chad R Schultz ₁ , Martin C H Gruhlke ₂ , Alan J Slusarenko ₂ , André S Bachmann ₁

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The natural product allicin is a reactive sulfur species (RSS) from garlic (Allium sativum L.). Neuroblastoma (NB) is an early childhood cancer arising from the developing peripheral nervous system. Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the biosynthesis of polyamines, which are oncometabolites that contribute to cell proliferation in NB and other c-MYC/MYCN-driven cancers. Both c-MYC and MYCN directly transactivate the E-box gene ODC1, a validated anticancer drug target. We identified allicin as a potent ODC inhibitor in a specific radioactive in vitro assay using purified human ODC. Allicin was ∼23 000-fold more potent (IC₅₀ = 11 nM) than DFMO (IC₅₀ = 252 μM), under identical in vitro assay conditions. ODC is a homodimer with 12 cysteines per monomer, and allicin reversibly S-thioallylates cysteines. In actively proliferating human NB cells allicin inhibited ODC enzyme activity, reduced cellular polyamine levels, inhibited cell proliferation (IC₅₀ 9–19 μM), and induced apoptosis. The natural product allicin is a new ODC inhibitor and could be developed for use in conjunction with other anticancer treatments, the latter perhaps at a lower than usual dosage, to achieve drug synergism with good prognosis and reduced adverse effects.

中文翻译：

大蒜素是神经母细胞瘤细胞中一种有效的新型鸟氨酸脱羧酶抑制剂。

天然产物大蒜素是来自大蒜 ( Allium sativum L.)的活性硫物质 (RSS )。神经母细胞瘤 (NB) 是一种由发育中的周围神经系统引起的儿童早期癌症。鸟氨酸脱羧酶 (ODC) 是多胺生物合成中的限速酶，多胺是促进 NB 和其他 c-MYC/MYCN 驱动的癌症中细胞增殖的代谢物。c-MYC 和 MYCN 都直接反式激活 E-box 基因ODC1，这是一种经过验证的抗癌药物靶点。我们在使用纯化的人 ODC的特定放射性体外测定中将大蒜素鉴定为有效的 ODC 抑制剂。_{在相同条件下，大蒜素的效力 (IC 50} = 11 nM) 是 DFMO (IC ₅₀ = 252 μM)的 23 000 倍体外测定条件。ODC 是一种同型二聚体，每个单体有 12 个半胱氨酸，大蒜素可逆地S-硫代烯丙基化半胱氨酸。在积极增殖的人 NB 细胞中，大蒜素抑制 ODC 酶活性，降低细胞多胺水平，抑制细胞增殖 (IC ₅₀ 9–19 μM)，并诱导细胞凋亡。天然产物大蒜素是一种新的 ODC 抑制剂，可以开发用于与其他抗癌治疗联合使用，后者的剂量可能低于通常的剂量，以实现药物协同作用，预后良好并减少不良反应。

更新日期：2020-08-28

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