Boesch Maximilian, Zeimet Alain G, Rumpold Holger, Gastl Guenther, Sopper Sieghart, Wolf Dominik
Institute of Immunobiology, St. Gallen, Switzerland; Tyrolean Cancer Research Institute, Innsbruck, Austria; Internal Medicine V and
Department of Gynecology and Obstetrics, Medical University Innsbruck, Innsbruck, Austria.
Stem Cells Transl Med. 2015 Sep;4(9):1028-32. doi: 10.5966/sctm.2015-0054. Epub 2015 Jul 1.
Ionophore antibiotics were reported to selectively kill cancer stem cells and to overcome multidrug resistance, but mechanistic studies of the significance of drug transporters for treatment with these compounds are lacking. We applied chemosensitivity testing of well-characterized human cancer cell lines to elaborate on whether drug transporters are involved in protection from the cytotoxic effects of the ionophore antibiotics salinomycin and nigericin. Our experiments demonstrated that ionophore antibiotics were ineffective against both stem-like ovarian cancer side population cells (expressing either ABCB1 or ABCG2) and K562/Dox-H1 cells, which constitute a genetically defined model system for ABCB1 expression. Considering that cancer stem cells often express high levels of drug transporters, we deduced from our results that ionophore antibiotics are less suited to cancer stem cell-targeted treatment than previously thought.
Ionophore antibiotics such as salinomycin have repeatedly been shown to target cancer stem and progenitor cells from various tumor entities. Meanwhile, cancer stem cell (CSC)-selective toxicity of ionophore antibiotics seems to be a commonly accepted concept that is about to encourage their clinical testing. This study provides data that challenge the concept of targeted elimination of CSC by ionophore antibiotics. Stem-like ovarian cancer side population (SP) cells expressing high levels of ABC drug transporters are shown to largely resist the cytotoxic effects of salinomycin and nigericin. Furthermore, using a small interfering RNA-based knockdown model specific for ABCB1, this study demonstrates that ABC drug transporters are indeed causally involved in mediating protection from ionophore antibiotics. Considering that it is a hallmark of CSCs to exhibit drug resistance conferred by ABC drug transporters, it must be deduced from these results that CSCs may also be protected from ionophore antibiotics by means of drug-transporter mediated efflux.
据报道，离子载体抗生素可选择性杀死癌症干细胞并克服多药耐药性，但缺乏关于药物转运蛋白在这些化合物治疗中作用的机制研究。我们对特征明确的人类癌细胞系进行化学敏感性测试，以阐明药物转运蛋白是否参与对离子载体抗生素盐霉素和尼日利亚菌素细胞毒性作用的保护。我们的实验表明，离子载体抗生素对干细胞样卵巢癌侧群细胞（表达ABCB1或ABCG2）和K562/Dox-H1细胞均无效，后者构成了ABCB1表达的基因定义模型系统。考虑到癌症干细胞通常高水平表达药物转运蛋白，我们从结果中推断，离子载体抗生素比之前认为的更不适合靶向治疗癌症干细胞。
盐霉素等离子载体抗生素已多次被证明可靶向来自各种肿瘤实体的癌症干细胞和祖细胞。同时，离子载体抗生素对癌症干细胞（CSC）的选择性毒性似乎是一个普遍接受的概念，这即将促使它们进行临床试验。本研究提供的数据对离子载体抗生素靶向消除CSC的概念提出了挑战。高水平表达ABC药物转运蛋白的干细胞样卵巢癌侧群（SP）细胞对盐霉素和尼日利亚菌素的细胞毒性作用具有很大抗性。此外，本研究使用针对ABCB1的基于小干扰RNA的敲低模型，证明ABC药物转运蛋白确实在介导对离子载体抗生素的保护中起因果作用。考虑到CSC的一个标志是表现出由ABC药物转运蛋白赋予的耐药性，从这些结果中必然可以推断出，CSC也可能通过药物转运蛋白介导的外排而免受离子载体抗生素的影响。
