Induction of apoptosis on ovarian adenocarcinoma cells, A2780 by tricyclohexylphosphanegold (I) mercaptobenzoate derivatives via intrinsic and extrinsic pathways,JBIC Journal of Biological Inorganic Chemistry

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Induction of apoptosis on ovarian adenocarcinoma cells, A2780 by tricyclohexylphosphanegold (I) mercaptobenzoate derivatives via intrinsic and extrinsic pathways
JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2021-09-03 , DOI: 10.1007/s00775-021-01892-6
Kok Pian Ang ₁ , Pit Foong Chan ₁ , Roslida Abd Hamid ₁

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Tricyclohexylphosphanegold(I) n-mercaptobenzoate (n = 2, 3, 4) labelled as 1–3 were previously reported to significantly suppress thioredoxin reductase (TrxR) activities towards ovarian cancer cells, A2780, in vitro. Herein, we explored the role of 1–3 for their apoptosis inducing ability against A2780 cells. 1–3 exhibited IC₅₀ values at 1.19 ± 0.03 µM, 2.28 ± 0.04 μM and 0.78 ± 0.01 μM, respectively, compared to cisplatin at 26.8 ± 0.15 µM. The compounds induced A2780 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by ROS production, cytochrome c release, caspases-3/7, -8, -9 and -10 activation, APAF1 and BAX upregulation as well as BCL2A1 and BCL2 genes’ downregulation. In addition, the death mode of 1–3 was also mediated via death receptor extrinsic pathway manifested by FAS, FASL, FADD, and TNFR1 genes’ upregulation via Human Rt PCR analysis. In addition, 1–3 significantly caused A2780 arrest at S phase, which was associated with the upregulation of TP53, E2F1, RB1 and CDKN1A upregulation and downregulation of CDK1, CDK4, CDC25A and CDC25C genes. Based on these promising results, these phosphanegold(I) thiolate derivatives could act as feasible candidates for further advanced in vivo ovarian cancer studies to develop novel chemotherapeutic agents derived from metal-based agents.

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中文翻译：

三环己基膦金 (I) 巯基苯甲酸酯衍生物通过内在和外在途径诱导卵巢腺癌细胞 A2780 凋亡

先前报道了标记为1-3的三环己基膦金 (I) n-巯基苯甲酸酯 ( n = 2, 3, 4)在体外显着抑制硫氧还蛋白还原酶 (TrxR) 对卵巢癌细胞 A2780 的活性。在此，我们探讨了1-3对 A2780 细胞的凋亡诱导能力的作用。1 – 3的IC ₅₀值分别为 1.19 ± 0.03 µM、2.28 ± 0.04 µM 和 0.78 ± 0.01 µM，而顺铂为 26.8 ± 0.15 µM。这些化合物通过半胱天冬酶依赖性线粒体途径诱导 A2780 细胞凋亡，如 ROS 产生、细胞色素c所证明的释放、caspase-3/7、-8、-9 和 -10 激活，APAF1和BAX上调以及BCL2A1和BCL2基因的下调。此外，通过人类 Rt PCR 分析， FAS、FASL、FADD和TNFR1基因的上调表明1-3的死亡模式也通过死亡受体外在途径介导。此外，1-3显着导致 A2780 在 S期停滞，这与TP53、E2F1、RB1和CDKN1A的上调有关CDK1、CDK4、CDC25A和CDC25C基因的上调和下调。基于这些有希望的结果，这些膦金（I）硫醇盐衍生物可以作为进一步先进的体内卵巢癌研究的可行候选者，以开发源自金属基药物的新型化学治疗剂。

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更新日期：2021-09-04

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