Experimental Oncology and Hemopathies Laboratory, Department of Clinical Analysis.
Post-Graduation Program in Pharmacy, Health Science Center.
Anticancer Drugs. 2019 Sep;30(8):828-837. doi: 10.1097/CAD.0000000000000780.
Acute leukemias are a heterogeneous group of aggressive malignant neoplasms associated with severe morbidities due to the nonselectivity of current chemotherapeutic drugs to nonmalignant cells. The investigation of novel natural and synthetic structures that might be used for the development of new drugs with greater efficiency and selectivity to leukemic cells is mandatory. In this context, thiosemicarbazones have been well described in the literature by their several biological properties and their reaction is known as versatile, low-cost, and highly chemoselective. With this perspective, this study aimed to investigate the cytotoxic effect and the main death mechanisms of a novel thiosemicarbazone (LAP17) on acute leukemia cell lines K562 and Jurkat. The results show that the strong cytotoxic effect of LAP17 to leukemic cells is due to apoptosis induction, which resulted in caspase-3 activation and DNA fragmentation. Intrinsic apoptosis seems to be related to the inversion of Bax/Bcl-2 expression, ΔΨm loss, and AIF release, whereas extrinsic apoptosis was initiated by FasR. Gene-expression profiling of HL-60 cells treated with LAP17 by the microarray technique revealed a significant enrichment of gene sets related to cell cycle arrest at G2/M. Accordingly, K562 and Jurkat cells treated with LAP17 revealed a clear arrest at G2/M phase. Taking into consideration that LAP17 was not cytotoxic to nonhematological cells (peripheral blood mononuclear cell and erythrocytes), these results suggest that LAP17 is a promising new compound that might be used as a prototype for the development of new antileukemic agents.
急性白血病是一组异质性的侵袭性恶性肿瘤，由于目前化疗药物对非恶性细胞缺乏选择性，导致严重的发病率和死亡率。因此，有必要研究新型天然和合成结构，这些结构可能被用于开发具有更高效率和选择性的白血病细胞的新药。在这方面，文献中已经很好地描述了硫代氨基甲缩醛的多种生物学特性，并且其反应具有多样性、低成本和高化学选择性等特点。基于这一观点，本研究旨在研究新型硫代氨基甲缩醛（LAP17）对急性白血病细胞系 K562 和 Jurkat 的细胞毒性作用和主要死亡机制。结果表明，LAP17 对白血病细胞的强烈细胞毒性作用是由于诱导细胞凋亡，导致 caspase-3 激活和 DNA 片段化。内源性凋亡似乎与 Bax/Bcl-2 表达的反转、ΔΨm 丧失和 AIF 释放有关，而外源性凋亡则是由 FasR 启动的。用微阵列技术对 HL-60 细胞进行 LAP17 处理后的基因表达谱分析显示，与 G2/M 期细胞周期阻滞相关的基因集显著富集。相应地，用 LAP17 处理的 K562 和 Jurkat 细胞明显停滞在 G2/M 期。考虑到 LAP17 对非造血细胞（外周血单核细胞和红细胞）没有细胞毒性，这些结果表明 LAP17 是一种很有前途的新化合物，可作为开发新的抗白血病药物的原型。
