PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC)\'s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized tris(3,5-dimethylphenyl)phosphonium-conjugated palmitic acid. Triphenylphosphonium (TPP) is a lipophilic cationic moiety that promotes the accumulation of conjugated agents in the mitochondrion. Palmitic acid (PA), the most common saturated fatty acid, has pro-apoptotic activity in different types of cancer cells. TPP-PA was prepared by the reaction of 16-bromopalmitic acid with TPP, and its structure was characterized by 1H and 13C NMR and HRMS. We compared the proteomes of TPP-PA-treated and untreated PDAC cells and PCSCs, identifying dysregulated proteins and pathways. Furthermore, assessments of mitochondrial membrane potential, intracellular ROS, cardiolipin content and lipid peroxidation, ER stress, and autophagy markers provided information on the mechanism of action of TPP-PA. The findings showed that TPP-PA reduces PDAC cell proliferation through mitochondrial disruption that leads to increased ROS, activation of ER stress, and autophagy. Hence, TPP-PA might offer a new approach for eliminating both the primary population of cancer cells and PCSCs, which highlights the promise of TPP-derived compounds as anticancer agents for PDAC.
摘要：
胰腺导管腺癌(PDAC)对治疗的抗性主要归因于胰腺癌干细胞(PCSCs)。线粒体损伤剂可用于阻碍PCSC繁殖并减少PDAC进展。因此,开发一种向线粒体输送药物的有效载体，我们合成了三（3,5-二甲基苯基）鳞共轭棕榈酸。三苯基鳞(TPP)是促进结合剂在线粒体中积累的亲脂性阳离子部分。棕榈酸(PA),最常见的饱和脂肪酸，在不同类型的癌细胞中具有促凋亡活性。通过16-溴棕榈酸与TPP的反应制备TPP-PA，并通过1H和13CNMR和HRMS对其结构进行了表征。我们比较了TPP-PA处理和未处理的PDAC细胞和PCSCs的蛋白质组,识别失调的蛋白质和途径。此外，评估线粒体膜电位，细胞内ROS，心磷脂含量和脂质过氧化，ER压力,和自噬标志物提供了关于TPP-PA作用机制的信息。研究结果表明，TPP-PA通过线粒体破坏减少PDAC细胞增殖，从而导致ROS增加，激活ER应激，和自噬。因此，TPP-PA可能为消除癌细胞和PCSCs的主要群体提供了一种新的方法，这凸显了TPP衍生化合物作为PDAC抗癌剂的前景。
