The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK.
The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK.
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曼德拉内酯是复杂的大内酯天然产物，具有独特的大环基序和生物活性谱，受复合糖基化的严重影响。Mandelalides A和B是线粒体ATP合成酶（复合体V）的直接抑制剂，因此对具有氧化代谢表型的哺乳动物细胞毒性更大。为了进一步了解扁桃醛类药物的药理作用，我们研究了amp激活的蛋白激酶（AMPK）能量应激途径，并报道了扁桃醛A是AMPK的间接激活剂。野生型小鼠胚胎成纤维细胞（mef）和具有代表性的人非小细胞肺癌（NSCLC）细胞对mandelalide a的反应显示，phospho-AMPK （Thr172）和phospho-ACC （Ser79）在U87-MG胶质母细胞瘤细胞中有统计学意义的增加，mandelalide L也具有a型大周期，诱导磷酸化- ampk （Thr172）和磷酸化- acc （Ser79）在U87-MG胶质母细胞瘤细胞中有类似的增加。相比之下，与AMPK抑制剂（dorsomorphin）、AMPKα-无效的mef或缺乏肝激酶B1 （LKB1）的NSCLC细胞共同处理的mef缺乏这种活性。与野生型细胞相比，Mandelalide A对AMPKα-缺失的MEFs具有更大的细胞毒性，这表明AMPK激活是对Mandelalide诱导的细胞ATP耗竭的保护性反应。然而，LKB1状态单独并不能预测曼德拉利A对NSCLC细胞的抗增殖作用。当考虑EGFR状态时，厄洛替尼和曼德拉利A联合对厄洛替尼耐药的11-18 NSCLC细胞显示出很强的细胞毒性协同作用，但对厄洛替尼敏感的PC-9细胞没有协同作用。最后，长期暴露于曼德拉胺A，一种强效的细胞毒素，对一组人类胶质母细胞瘤细胞类型有效，而不管细胞的潜在代谢表型。这些结果增加了曼德拉利系列的生物学相关性，并为其作为ATP合成酶抑制剂和AMPK二级激活剂的进一步临床前评估提供了基础。
The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
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影响因子：
7.7
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4.3
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11.5
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