Cationic block amphiphiles show anti-mitochondrial activity in multi-drug resistant breast cancer cells
Cationic block amphiphiles show anti-mitochondrial activity in multi-drug resistant breast cancer cells
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DOI：
10.1016/j.jconrel.2019.04.045
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发表时间：
2019-07-10
影响因子：
10.8
通讯作者：
Shoichet, Molly S.
中科院分区：
文献类型：
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作者：
Czupiel, Petro P.;Delplace, Vianney;Shoichet, Molly S.
目前，对多药耐药乳腺癌的治疗选择有限。脂质修饰的阳离子肽具有到达线粒体的潜力，线粒体是治疗多药耐药（MDR）乳腺癌的有吸引力的靶点;然而，对其线粒体靶向和抗癌活性知之甚少。有趣的是，通常用作基因转染剂的脂质修饰的阳离子肽表现出与线粒体靶向肽相似的结构特征。我们使用八组氨酸-八精氨酸（H8 R8）作为细胞渗透和内体逃逸的模型阳离子肽，探索了脂质修饰的阳离子肽的抗癌潜力与两亲性、生物降解性和脂质结构的关系。我们发现，用长度至少为12个碳的脂质修饰的阳离子肽在EMT 6/P和EMT 6/AR-1乳腺癌细胞中在低微摩尔范围内表现出有效的抗癌活性。比较可降解和不可降解的接头，以及L-和D-氨基酸序列，我们发现，抗癌活性主要是独立的脂质修饰的阳离子肽的生物降解。两种候选物，硬脂酰-H8 R8（Str-H8 R8）和维生素E琥珀酸酯-H8 R8（VES-H8 R8）通过线粒体去极化对癌细胞具有细胞毒性。我们观察到活性氧（ROS）的产生增加，细胞生物能量学和药物外排减少，引发细胞凋亡和G1期细胞周期阻滞。与Str-H8 R8相比，VES-H8 R8显示出增强的癌细胞选择性和药物外排抑制，从而用作潜在的新型治疗剂。这项研究加深了我们对脂质修饰的阳离子肽的理解，并揭示了它们在多药耐药乳腺癌中的潜力。
Currently, there are limited treatment options for multi-drug resistant breast cancer. Lipid-modified cationic peptides have the potential to reach the mitochondria, which are attractive targets for the treatment of multidrug resistant (MDR) breast cancer; yet, little is known about their mitochondrial targeting and anti-cancer activity. Interestingly, lipid-modified cationic peptides, typically used as gene transfection agents, exhibit similar structural features to mitochondrial targeted peptides. Using octahistidine-octaarginine (H8R8) as a model cationic peptide for cell penetration and endosomal escape, we explored the anti-cancer potential of lipid-modified cationic peptides as a function of amphiphilicity, biodegradability and lipid structure. We found that cationic peptides modified with a lipid that is at least 12 carbons in length exhibit potent anti-cancer activity in the low micromolar range in both EMT6/P and EMT6/AR-1 breast cancer cells. Comparing degradable and non-degradable linkers, as well as L- and D-amino acid sequences, we found that the anti-cancer activity is mostly independent of the biodegradation of the lipid-modified cationic peptides. Two candidates, stearyl-H8R8 (Str-H8R8) and vitamin E succinate-H8R8 (VES-H8R8) were cytotoxic to cancer cells by mitochondria depolarization. We observed increased reactive oxygen species (ROS) production, reduced cell bioenergetics and drug efflux, triggering apoptosis and G1 cell cycle arrest. Compared to Str-H8R8, VES-H8R8 showed enhanced cancer cell selectivity and drug efflux inhibition, thereby serving as a potential novel therapeutic agent. This study deepens our understanding of lipid-modified cationic peptides and uncovers their potential in multi-drug resistant breast cancer.