Stefanes Natália Marcéli, de Oliveira Silva Lisandra, Walter Laura Otto, Steimbach João Vitor, Markendorf Emanueli, Ribeiro Amanda Abdalla Biasi, Feuser Paulo Emílio, Cordeiro Arthur Poester, Santos-Silva Maria Cláudia
Experimental Oncology and Hemopathies Laboratory, Department of Clinical Analysis, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, 88040-900, SC, Brazil.
Graduate Program in Pharmacy, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, 88040-900, SC, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb;398(2):1871-1882. doi: 10.1007/s00210-024-03399-8. Epub 2024 Aug 26.
Myeloid leukemias and lymphomas are among the most common and well-studied hematological malignancies. However, due to the aggressiveness and rapid progression of certain subtypes, treating these diseases remains a challenge. Considering the promising results of diethyldithiocarbamates in preclinical and clinical oncology trials, this study aimed to investigate the potential of sodium diethyldithiocarbamate trihydrate (DETC) as a prototype for developing new drugs to treat hematological malignancies. In silico analysis using SwissADME was conducted to evaluate the physicochemical characteristics and pharmacokinetic properties of DETC. An in vitro investigation utilizing the MTT assay assessed the cytotoxic effects of DETC on neoplastic and non-neoplastic cell lines. Selectivity was determined using a selectivity index and a hemolysis assay, while the mechanism of cell death in neoplastic cell lines was examined through flow cytometry analysis of pro-apoptotic and anti-apoptotic protein levels. The results demonstrated that the physicochemical characteristics of DETC are suitable for oral administration. Furthermore, the compound showed promising cytotoxic activity against human myeloid leukemia (K562) and Burkitt's lymphoma (Daudi) cell lines, with high selectivity for neoplastic cells over non-neoplastic cells of the bone marrow microenvironment (HS-5 cell line). Moreover, hemolysis was observed only at very high concentrations. The cytotoxicity mechanism of DETC against both neoplastic cell lines involved cell cycle arrest and the production of reactive oxygen species. In K562 cells, cell death was induced via apoptosis. Additional experiments are needed to confirm the exact mechanism of cell death in Daudi Burkitt's lymphoma cells.
髓系白血病和淋巴瘤是最常见且研究充分的血液系统恶性肿瘤。然而，由于某些亚型具有侵袭性且进展迅速，治疗这些疾病仍然是一项挑战。鉴于二乙基二硫代氨基甲酸盐在临床前和临床肿瘤学试验中取得了有前景的结果，本研究旨在探究三水合二乙基二硫代氨基甲酸钠（DETC）作为开发治疗血液系统恶性肿瘤新药原型的潜力。使用SwissADME进行了计算机模拟分析，以评估DETC的物理化学特性和药代动力学性质。利用MTT法进行的体外研究评估了DETC对肿瘤细胞系和非肿瘤细胞系的细胞毒性作用。使用选择性指数和溶血试验确定选择性，同时通过对促凋亡和抗凋亡蛋白水平的流式细胞术分析来研究肿瘤细胞系中的细胞死亡机制。结果表明，DETC的物理化学特性适合口服给药。此外，该化合物对人髓系白血病（K562）和伯基特淋巴瘤（Daudi）细胞系显示出有前景的细胞毒性活性，对肿瘤细胞的选择性高于骨髓微环境的非肿瘤细胞（HS - 5细胞系）。而且，仅在非常高的浓度下才观察到溶血现象。DETC对两种肿瘤细胞系的细胞毒性机制涉及细胞周期阻滞和活性氧的产生。在K562细胞中，细胞死亡是通过凋亡诱导的。需要进一步的实验来确认Daudi伯基特淋巴瘤细胞中细胞死亡的确切机制。
