Glycolysis inhibitor screening identifies the bis-geranylacylphloroglucinol protonophore moronone from Moronobea coccinea.
Glycolysis inhibitor screening identifies the bis-geranylacylphloroglucinol protonophore moronone from Moronobea coccinea.
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DOI：
10.1021/np300711e
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发表时间：
2012-12-28
影响因子：
5.1
通讯作者：
Zhou YD
中科院分区：
文献类型：
--
作者：
Datta S;Li J;Mahdi F;Jekabsons MB;Nagle DG;Zhou YD
肿瘤细胞表现出增强的葡萄糖消耗和乳酸盐产生，即使在提供足够的氧气时（一种称为瓦尔堡效应或有氧糖酵解的现象）。有氧糖酵解的药理学抑制代表了一种潜在的肿瘤选择性方法，其靶向正常和恶性组织之间的代谢差异。使用人乳腺肿瘤MDA-MB-231细胞开发测定系统以发现基于天然产物的糖酵解抑制剂。所采用的测定是基于用线粒体电子传递抑制剂鱼藤酮处理的肿瘤细胞对糖酵解抑制的超敏反应。在这种条件下，ATP的供应，因此细胞的活力，完全取决于糖酵解。该分析系统用于评估来自美国国家癌症研究所开放库的10，648种植物和海洋生物提取物。活性Moronobea cocccoba提取物的生物测定引导分离产生了新的双-香叶基酰基间苯三酚衍生物moronone（1）。化合物1在鱼藤酮对肿瘤细胞施加的代谢应激存在下表现出增强的抗增殖/细胞毒性活性。令人惊讶的是，机制研究表明，1不抑制糖酵解，而是作为一个质子载体，消散线粒体质子梯度的功能。在鱼藤酮的存在下，由于ATP合酶增加ATP利用，肿瘤细胞可能对质子载体过敏。
Tumor cells exhibit enhanced glucose consumption and lactate production even when supplied with adequate oxygen (a phenomenon known as the Warburg effect, or aerobic glycolysis). Pharmacological inhibition of aerobic glycolysis represents a potential tumor-selective approach that targets the metabolic differences between normal and malignant tissues. Human breast tumor MDA-MB-231 cells were used to develop an assay system to discover natural product-based glycolysis inhibitors. The assay employed was based on hypersensitivity to glycolytic inhibition in tumor cells treated with the mitochondrial electron transport inhibitor rotenone. Under such conditions, ATP supply, and hence cell viability, depends exclusively on glycolysis. This assay system was used to evaluate 10,648 plant and marine organism extracts from the U.S. National Cancer Institute's Open Repository. Bioassay-guided isolation of an active Moronobea coccinea extract yielded the new bis-geranylacylphloroglucinol derivative moronone (1). Compound 1 exhibited enhanced antiproliferative/cytotoxic activity in the presence of rotenone-imposed metabolic stress on tumor cells. Surprisingly, mechanistic studies revealed that 1 did not inhibit glycolysis, but rather functions as a protonophore that dissipates the mitochondrial proton gradient. In the presence of rotenone, tumor cells may be hypersensitive to protonophores due to increased ATP utilization by the ATP synthase.
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
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影响因子：
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通讯作者：
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