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Molecular mechanisms of apoptosis induction in K562 and KG1a leukemia cells by a water-soluble copper(II) thiosemicarbazone complex.
JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2020-04-09 , DOI: 10.1007/s00775-020-01769-0
Fatemeh Ghorbani Parsa 1 , Mohammad Ali Hosseinpour Feizi 1 , Reza Safaralizadeh 1 , Seyed Abolfazl Hosseini-Yazdi 2 , Majid Mahdavi 1
Affiliation  

Abstract

Thiosemicarbazones (TSCs) and their metal complexes exhibit pronounced and selective cytotoxic potential against a broad span of cancers. Here, we assessed the anti-cancer activity of a water-soluble copper(II) complex of thiosemicarbazone (Cu-TSC) against two cancer cell lines of human leukemia. Our analysis revealed that Cu-TSC treatment results in a time and dose-dependent growth inhibition in K562 and KG1a cells while sparing normal human fibroblast (HFF2) cells. The IC50 values for the Cu-TSC treatment were measured to be 21.7 ± 1.5 µM and 50.25 ± 2.5 µM for K562 and KG1a cells, respectively. Cell cycle analysis indicated that Cu-TSC induces the accumulation of cells in the sub-G1 fraction as well as the reversible arrest in G0/G1 and G2/M phases in K562 and KG1a cells, respectively. Furthermore, the occurrence of apoptosis as the prime mode of cell death was verified through apoptotic body formation, phosphatidylserine externalization, and caspase-3 activation. Additionally, the real-time quantitative PCR analysis revealed that Cu-TSC triggers apoptosis in both cell lines via the upregulation of caspases-8, -9, and the changing of Bax/Bcl2 ratio. Finally, flow cytometric analysis confirmed that Cu-TSC treatment causes the enhancement of reactive oxygen species formation in both K562 and KG1a cells. Altogether, these findings suggest that Cu-TSC is a promising inducer of apoptosis in leukemia cells and carries potential as an anti-cancer compound.

Graphic abstract



中文翻译:

水溶性铜(II)硫代半碳zone复合物诱导K562和KG1a白血病细胞凋亡的分子机制。

摘要

硫代氨基咔唑(TSC)及其金属配合物对多种癌症均表现出明显的选择性细胞毒性潜力。在这里,我们评估了硫半脲(Cu-TSC)的水溶性铜(II)配合物对人类白血病的两种癌细胞系的抗癌活性。我们的分析表明,Cu-TSC处理可导致K562和KG1a细胞受到时间和剂量依赖性的生长抑制,而保留正常的人类成纤维细胞(HFF2)细胞。IC 50对于K562和KG1a细胞,测量的Cu-TSC值分别为21.7±1.5 µM和50.25±2.5 µM。细胞周期分析表明,Cu-TSC诱导亚G1部分中的细胞蓄积,并分别诱导K562和KG1a细胞中G0 / G1和G2 / M期的可逆停滞。此外,通过凋亡小体的形成,磷脂酰丝氨酸的外在化和caspase-3的活化,可以证实凋亡是细胞死亡的主要方式。此外,实时定量PCR分析表明,Cu-TSC通过上调caspases-8,-9和Bax / Bcl2比的变化来触发两种细胞系的凋亡。最后,流式细胞仪分析证实,Cu-TSC处理可增加K562和KG1a细胞中活性氧的形成。共,

图形摘要

更新日期:2020-04-09
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