Ultrashort cationic lipopeptides and lipopeptoids: Evaluation and mechanistic insights against epithelial cancer cells
Ultrashort cationic lipopeptides and lipopeptoids: Evaluation and mechanistic insights against epithelial cancer cells
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DOI：
10.1016/j.peptides.2016.07.007
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发表时间：
2016-10-01
期刊：
影响因子：
3
通讯作者：
Schweizer, Frank
中科院分区：
文献类型：
--
作者：
Domalaon, Ronald;Findlay, Brandon;Schweizer, Frank
由于多肽的可及性和易修饰性，为开发新的抗癌先导剂提供了一个有吸引力的支架。合成超短阳离子脂肽是为了在较小的分子尺寸内保持较长多肽的生物活性而开发的，它与一个脂肪酸的偶联氨基酸不超过四个。在此，我们报道了两亲性脂三肽、脂三肽和脂四肽对乳腺(MDA-M13-231，JIMT-1)、前列腺癌(DU145)和胰腺癌细胞(MiaPaCa2)的抑制作用。经鉴定，C16-KKK-NH2和C16-PCatPHexPCat-NH2脂三肽具有抗癌活性。后者是由两个L-4R-氨基脯氨酸(P-Cat)和两个L-4R-己氧脯氨酸(P-Hex)组成的短多聚脯氨酸骨架。然而，所有制备的脂三肽都没有抗癌活性。两亲性C16-PCatPHexPHexPCat-NH2的抗癌活性与表面活性剂苯乙氯铵相似，但活性优于肉豆蔻胺。机制研究表明，这些多肽不能溶解绵羊红细胞，也不能溶解上皮癌细胞，因此排除了坏死是细胞死亡的机制。令人惊讶的是，这两种脂肽显示出不同的导致癌细胞死亡的作用机制。脂三肽C16-KKK-NH2可诱导caspase介导的细胞凋亡，而C16-PCatPHexPHexPCat-NH2可不依赖于caspase而杀伤肿瘤细胞。(C)2016 Elsevier Inc.保留所有权利。
Peptides present an attractive scaffold for the development of new anticancer lead agents due to their accessibility and ease of modification. Synthetic ultrashort cationic lipopeptides, with four amino acids or less conjugated to a fatty acid, were developed to retain the biological activity of longer peptides in a smaller molecular size. Herein, we report the activity of amphiphilic lipotripeptides, lipotripeptoids and lipotetrapeptides against breast (MDA-M13-231, JIMT-1), prostate (DU145) and pancreas (MiaPaCa2) epithelial cancer cell lines. The lipotripeptide C16-KKK-NH2 and lipotetrapeptide C16-PCatPHexPCat-NH2 were identified to possess anticancer activity. The latter lipotetrapeptide possess a short polyproline scaffold consisting of only two L-4R-aminoproline (P-Cat) and two L-4R-hexyloxyproline (P-Hex). However, all the prepared lipotripeptoids lack anticancer activity. The amphiphilic C16-PCatPHexPHexPCat-NH2 exhibited similar anticancer potency to the surfactant benzethonium chloride while superior activity was observed in comparison to myristylamine. Mechanistic studies revealed that the peptides do not lyse ovine erythrocytes nor epithelial cancer cells, thus ruling out necrosis as the mechanism of cell death. Surprisingly, the two lipopeptides exhibit different mechanisms of action that result in cancer cell death. The lipotripeptide C16-KKK-NH2 was found to induce caspase-mediated apoptosis while C16-PCatPHexPHexPCat-NH2 kills tumor cells independent of caspases. (C) 2016 Elsevier Inc. All rights reserved.