Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61‒614 Poznań, Poland.
Biomed Pharmacother. 2018 Mar;99:384-390. doi: 10.1016/j.biopha.2018.01.081.
Salinomycin (SAL) and monensin (MON) are polyether ionophore antibiotics commonly used in veterinary medicine. They are known from their anti-cancer activity against various types of cancer cells, including those that display multi-drug resistance as well as cancer stem cells. In order to increase the biological activity profile and reduce toxicity against normal cells, while retaining the activities in the micromolar range, a library of ester and amide derivatives of SAL was synthesized and previously reported. In this paper, we examined the activity of SAL, its ten derivatives, and MON on primary acute lymphoblastic leukemia cells. MON and six SAL derivatives were more potent than SAL in cell viability assays. Further, selected active SAL analogs induced characteristics of apoptotic cell death and increased expression of p53. Moreover, SAL acted synergistically with the Bcl-2 inhibitor ABT-263, whereas 2,2,2-trifluoroethyl ester, the most active analog of SAL, antagonized ABT-263, suggesting possible differences in molecular mechanism.
盐霉素（SAL）和莫能菌素（MON）是兽医中常用的聚醚离子载体抗生素。它们具有抗多种癌细胞的抗癌活性，包括多药耐药性癌细胞和癌症干细胞。为了提高生物活性谱并降低对正常细胞的毒性，同时保留在微摩尔范围内的活性，已经合成并先前报道了 SAL 的酯和酰胺衍生物库。在本文中，我们研究了 SAL、其十个衍生物和 MON 对原代急性淋巴细胞白血病细胞的活性。在细胞活力测定中，MON 和六个 SAL 衍生物比 SAL 更有效。此外，选定的活性 SAL 类似物诱导了凋亡细胞死亡的特征，并增加了 p53 的表达。此外，SAL 与 Bcl-2 抑制剂 ABT-263 协同作用，而 SAL 最有效的类似物 2,2,2-三氟乙基酯拮抗 ABT-263，表明可能存在分子机制上的差异。
