Montalbano Serena, Bisceglie Franco, Pelosi Giorgio, Lazzaretti Mirca, Buschini Annamaria
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.
COMT (Interdepartmental Centre for Molecular and Translational Oncology), University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.
Pharmaceutics. 2023 Apr 24;15(5):1325. doi: 10.3390/pharmaceutics15051325.
Since the discovery of cisplatin, the search for metal-based compounds with therapeutic potential has been a challenge for the scientific community. In this landscape, thiosemicarbazones and their metal derivatives represent a good starting point for the development of anticancer agents with high selectivity and low toxicity. Here, we focused on the action mechanism of three metal thiosemicarbazones [Ni(tcitr)], [Pt(tcitr)], and [Cu(tcitr)], derived from citronellal. The complexes were already synthesized, characterized, and screened for their antiproliferative activity against different cancer cells and for genotoxic/mutagenic potential. In this work, we deepened the understanding of their molecular action mechanism using an in vitro model of a leukemia cell line (U937) and an approach of transcriptional expression profile analysis. U937 cells showed a significant sensitivity to the tested molecules. To better understand DNA damage induced by our complexes, the modulation of a panel of genes involved in the DNA damage response pathway was evaluated. We analyzed whether our compounds affected cell cycle progression to determine a possible correlation between proliferation inhibition and cell cycle arrest. Our results demonstrate that metal complexes target different cellular processes and could be promising candidates in the design of antiproliferative thiosemicarbazones, although their overall molecular mechanism is still to be understood.
自从顺铂被发现以来，寻找具有治疗潜力的金属基化合物一直是科学界面临的一项挑战。在这种情况下，硫代氨基脲及其金属衍生物是开发具有高选择性和低毒性的抗癌药物的一个良好起点。在此，我们重点研究了三种源自香茅醛的金属硫代氨基脲[Ni(tcitr)]、[Pt(tcitr)]和[Cu(tcitr)]的作用机制。这些配合物已经合成、表征，并针对它们对不同癌细胞的抗增殖活性以及遗传毒性/致突变潜力进行了筛选。在这项工作中，我们使用白血病细胞系（U937）体外模型和转录表达谱分析方法，加深了对其分子作用机制的理解。U937细胞对所测试的分子表现出显著的敏感性。为了更好地理解我们的配合物诱导的DNA损伤，我们评估了参与DNA损伤反应途径的一组基因的调控情况。我们分析了我们的化合物是否影响细胞周期进程，以确定增殖抑制与细胞周期停滞之间可能存在的相关性。我们的结果表明，金属配合物靶向不同的细胞过程，尽管其整体分子机制仍有待了解，但它们可能是设计抗增殖硫代氨基脲的有前途的候选物。
