The natural product family of macrocyclic lipodepsipeptides containing the 4-amido-2,4-pentadienoate functionality possesses intriguing cytotoxic selectivity toward hypoxic cancer cells. These subpopulations of cancer cells display increased metastatic potential and resistance to chemo- and radiotherapy. In this paper, we present studies on the mechanism of action of these natural products in hypoxic cancer cells and show that this involves rapid and hypoxia-selective collapse of mitochondrial integrity and function. These events drive a regulated cell death process that potentially could function as a powerful tool in the fight against chemo- and radiotherapy-resistant cancer cells. Toward that end, we demonstrate activity in two different mouse tumor models.

中文翻译：

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含APD的脂环肽肽靶向缺氧癌细胞中的线粒体功能

含有4-酰胺基-2,4-戊二烯酸酯官能团的大环脂肽肽的天然产物家族对低氧癌细胞具有令人感兴趣的细胞毒性选择性。这些癌细胞亚群显示出增加的转移潜力以及对化学疗法和放射疗法的抵抗力。在本文中，我们对这些天然产物在低氧癌细胞中的作用机理进行了研究，并表明这涉及线粒体完整性和功能的快速缺氧选择性崩溃。这些事件推动了细胞死亡的调控过程，该过程有可能成为抵抗化学和放射治疗耐药性癌细胞的有力工具。为此，我们证明了在两种不同的小鼠肿瘤模型中的活性。