Abdul Razak Nabiha Hidayah, Rasli Nur Rasyiqin, Mohamad Zamri Norsyahira, Hamid Asmah, Awang Normah, Kamaludin Nurul Farahana
Program of Biomedical Science, Center for Toxicology & Health Risk Study (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
Environmental Health & Industrial Safety Program, Center for Toxicology & Health Risk Study (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
PLoS One. 2025 Aug 11;20(8):e0329860. doi: 10.1371/journal.pone.0329860. eCollection 2025.
Acute lymphoblastic leukemia (ALL) is a common cancer affecting children worldwide, and current treatment has adverse effects such as neurotoxicity. To overcome this problem, new organotin (IV) dithiocarbamate compounds were synthesized. In this study, the T-lymphoblastic leukemia cell line (CCL-119) was tested against seven new compounds: diphenyltin (IV) diisopropyl dithiocarbamate (ODTC 1), diphenyltin (IV) diallyl dithiocarbamate (ODTC 2), triphenyltin (IV) diisopropyl dithiocarbamate (ODTC 3), triphenyltin (IV) diallyl dithiocarbamate (ODTC 4), triphenyltin (IV) diethyl dithiocarbamate (ODTC 5), dimethyltin (IV) diisopropyl dithiocarbamate (ODTC 6) and dimethyltin (IV) diethyl dithiocarbamate (ODTC 7) hereafter referred to as ODTC 1-7, to identify their cytotoxic effects (MTT assay), mode of cell death (Annexin V FITC/PI staining) and effects on the cell cycle (RNase/PI staining) as well as genotoxic effects (alkaline comet assay). Results obtained after 24 hours of exposure showed that all organotin (IV) dithiocarbamate compounds (ODTC 1-7) exhibited potent cytotoxicity, with median inhibitory concentration (IC50) values ranging from 0.18 µM to 3.10 µM. The selectivity index showed that diphenyltin (IV) and triphenyltin (IV) dithiocarbamate compounds are more selective towards CCL-119 cells. All ODTC compounds induced apoptosis in CCL-119 cells, and each compound caused cell cycle arrest at specific phases, indicating diverse mechanisms of action. Apoptosis and cell cycle arrest were confirmed by flow cytometry. Treatment of the compounds caused significant (p < 0.05) DNA damage compared to the negative control, with ODTC 1 causing the highest genotoxic effects. In conclusion, diphenyltin (IV) and triphenyltin (IV) dithiocarbamate compounds show good potential as anti-leukemia agents. However, further studies on the mechanisms of action need to be conducted to have better insights into the effect of this compound on CCL-119 leukemia cells.
急性淋巴细胞白血病（ALL）是一种在全球范围内影响儿童的常见癌症，目前的治疗存在神经毒性等不良反应。为克服这一问题，合成了新型有机锡（IV）二硫代氨基甲酸盐化合物。在本研究中，使用T淋巴细胞白血病细胞系（CCL - 119）对七种新型化合物进行了测试：二苯基锡（IV）二异丙基二硫代氨基甲酸盐（ODTC 1）、二苯基锡（IV）二烯丙基二硫代氨基甲酸盐（ODTC 2）、三苯基锡（IV）二异丙基二硫代氨基甲酸盐（ODTC 3）、三苯基锡（IV）二烯丙基二硫代氨基甲酸盐（ODTC 4）、三苯基锡（IV）二乙基二硫代氨基甲酸盐（ODTC 5）、二甲基锡（IV）二异丙基二硫代氨基甲酸盐（ODTC 6）和二甲基锡（IV）二乙基二硫代氨基甲酸盐（ODTC 7），以下统称为ODTC 1 - 7，以确定它们的细胞毒性作用（MTT法）、细胞死亡模式（膜联蛋白V FITC/PI染色）、对细胞周期的影响（核糖核酸酶/PI染色）以及遗传毒性作用（碱性彗星试验）。暴露24小时后获得的结果表明，所有有机锡（IV）二硫代氨基甲酸盐化合物（ODTC 1 - 7）均表现出强大的细胞毒性，半数抑制浓度（IC50）值范围为0.18 μM至3.10 μM。选择性指数表明，二苯基锡（IV）和三苯基锡（IV）二硫代氨基甲酸盐化合物对CCL - 119细胞更具选择性。所有ODTC化合物均诱导CCL - 119细胞凋亡，且每种化合物均使细胞周期在特定阶段停滞，表明其作用机制多样。通过流式细胞术证实了细胞凋亡和细胞周期停滞。与阴性对照相比，化合物处理导致显著（p < 0.05）的DNA损伤，其中ODTC 1造成的遗传毒性作用最强。总之，二苯基锡（IV）和三苯基锡（IV）二硫代氨基甲酸盐化合物显示出作为抗白血病药物的良好潜力。然而，需要对其作用机制进行进一步研究，以更好地了解该化合物对CCL - 119白血病细胞的影响。
