Biological activity of doubly modified salinomycin analogs - Evaluation in vitro and ex vivo
Biological activity of doubly modified salinomycin analogs - Evaluation in vitro and ex vivo
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DOI：
10.1016/j.ejmech.2018.07.021
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发表时间：
2018-08-05
影响因子：
6.7
通讯作者：
Strand, Daniel
中科院分区：
文献类型：
--
作者：
Antoszczak, Michal;Urbaniak, Alicja;Strand, Daniel
盐霉素是一种新型的离子载体，由于其对多药耐药癌细胞和肿瘤干细胞的抑制作用，近年来引起了人们的广泛关注。先前的研究已经表明，C20位置的酰化或C1羧酸酯部分的酯化/酰胺化在生物学性质方面是有益的。在本文中，我们提出了第一个类似物结合这样的修改。对一系列癌细胞系的抗增殖活性的评价表明，C20羟基的酰化提高了盐霉素C1酰胺的活性，但没有相应的C1酯的活性。重要的是，在LoVo/DX多药耐药细胞系中，几种双重修饰的类似物的活性超过了常用的细胞抑制药物顺铂和多柔比星的活性。所有类似物都在标准细胞活力测定中针对原代急性淋巴细胞白血病细胞进行了测试;其中三种比盐霉素更有效。进一步的研究表明，所选的类似物诱导凋亡性细胞死亡和增加p53表达的特征。此外，使用乳腺肿瘤的离体模型，在用盐霉素或其双重修饰的衍生物（3a）处理后，肿瘤细胞活力以时间依赖性方式显著降低。目前的研究结果表明，双修饰盐霉素衍生物构成有前途的铅化合物，针对各种类型的癌症。(C)2018年Elsevier Masson SAS。All rights reserved.
The polyether ionophore salinomycin has recently captured much interest due to its potent activity against multi-drug resistant cancer cells and cancer stem cells. Previous studies have shown that either acylation of the C20 position or esterification/amidation of the C1 carboxylate moiety is beneficial in terms of biological properties. In this paper, we present the first analogs combining such modifications. Evaluation of the anti-proliferative activity against a series of cancer cell lines showed that acylation of the C20 hydroxyl group improves the activity of salinomycin C1 amides but not of the corresponding C1 esters. Importantly, the activity of several of the doubly modified analogs surpasses that of commonly used cytostatic drugs cisplatin and doxorubicin in the LoVo/DX multi-drug resistant cell line. All analogs were tested against primary acute lymphoblastic leukemia cells in standard cell viability assays; three were more potent than salinomycin. Further studies revealed that selected analogs induced characteristics of apoptotic cell death and increased expression of p53. Additionally, using an ex vivo model of breast tumor, tumor cell viability significantly decreased after treatment with salinomycin or its double modified derivative (3a) in a time-dependent manner. The present findings indicate that double modified salinomycin derivatives constitute promising lead compounds for targeting various types of cancer. (C) 2018 Elsevier Masson SAS. All rights reserved.