Czubatka-Bieńkowska Anna, Sarnik Joanna, Macieja Anna, Galita Grzegorz, Witczak Zbigniew J, Poplawski Tomasz
Department of Molecular Genetics, University of Lodz, Lodz 90-236, Poland.
Department of Pharmaceutical Sciences, Nesbitt School of Pharmacy, Wilkes University, 84 W. South Street, Wilkes-Barre, PA 18766, USA.
Bioorg Med Chem Lett. 2017 Jun 15;27(12):2713-2720. doi: 10.1016/j.bmcl.2017.04.051. Epub 2017 Apr 21.
Thiosemicarbazides and their analogs have shown potential medical applications as antiviral, antibacterial and anticancer drugs. We designed, synthesized and evaluated in vitro anticancer activity against ovarian (A2780), cervix (HeLa), colon (LoVo), breast (MCF-7) and brain (MO59J) human cancer cell lines of seven novel compounds -S-glycosylated thiosemicarbazones. We assessed the cyto- and genotoxic properties of all novel compounds using a variety of methods including comet assay, XTT assay, various fluorescent assays and toxicology PathwayFinder expression array. We tried to evaluate their possible mechanism of action with particular attention to induction of DNA damage and repair, apoptosis, oxidative stress analysis and cellular response in terms of changes in gene expression. The most sensitive cell line was human ovarian cancer. The results revealed that the major activity against A2780 cancer cell line displayed by our compounds is induction of DNA damage. This effect is not associated with apoptosis or oxidative stress induction and the resulting damage will not lead to cell cycle arrest. We also observed up-expression of heat shock related genes and NQO1 gene in response to our compounds. The second effect seems to be specific to glycosylated S-bond compounds as we observed it earlier. Upregulation of heat shock protein encoding genes suggest that our compounds induce stressful conditions. The nature of this phenomena (heat shock, pH shift or hypoxia) needs further study.
硫代氨基脲及其类似物已显示出作为抗病毒、抗菌和抗癌药物的潜在医学应用。我们设计、合成并在体外评估了七种新型化合物——S-糖基化硫代氨基脲对卵巢（A2780）、宫颈（HeLa）、结肠（LoVo）、乳腺（MCF-7）和脑（MO59J）人癌细胞系的抗癌活性。我们使用多种方法评估了所有新型化合物的细胞毒性和遗传毒性特性，包括彗星试验、XTT试验、各种荧光试验和毒理学途径发现者表达阵列。我们试图评估它们可能的作用机制，特别关注DNA损伤和修复的诱导、凋亡、氧化应激分析以及基因表达变化方面的细胞反应。最敏感的细胞系是人类卵巢癌。结果表明，我们的化合物对A2780癌细胞系的主要活性是诱导DNA损伤。这种效应与凋亡或氧化应激诱导无关，所产生的损伤也不会导致细胞周期停滞。我们还观察到热休克相关基因和NQO1基因在对我们的化合物的反应中上调。第二种效应似乎是糖基化S键化合物特有的，因为我们之前就观察到了。热休克蛋白编码基因的上调表明我们的化合物诱导了应激条件。这种现象（热休克、pH值变化或缺氧）的性质需要进一步研究。
