PGV-1 导致纺锤体微管组织混乱,导致 HLF 和 HuH6 细胞有丝分裂异常,并与 MYCN 状态改变有关。

IF 3.1 Q2 PHARMACOLOGY & PHARMACY Advanced pharmaceutical bulletin Pub Date : 2024-10-01 Epub Date: 2024-07-31 DOI:10.34172/apb.2024.058
Nadzifa Nugraheni, Ummi Maryam Zulfin, Beni Lestari, Novia Permata Hapsari, Muthi Ikawati, Rohmad Yudi Utomo, Yusuke Suenaga, Yoshitaka Hippo, Edy Meiyanto
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引用次数: 0

摘要

目的:HLF和HuH-6细胞系代表肝细胞癌(HCC),其染色体含量的不同可能导致不同的药物反应。在此,PGV-1 试图挑战其对 HLF 和 HuH-6 的生长抑制作用,并追踪其与索拉非尼相比的分子靶点作用机制:方法:采用MTT细胞毒性试验、集落形成试验、流式细胞术分析、免疫荧光试验和Western blot试验:结果:PGV-1 对 HLF 和 HuH-6 具有细胞毒性作用,IC-50 值分别为 1 µM 和 2 µM,而索拉非尼的细胞毒性较弱,IC-50 值分别为 5 µM 和 8 µM。PGV-1 能永久抑制细胞生长,而索拉非尼则不能。索拉非尼没有改变两种细胞的细胞周期图谱,但 PGV-1 使细胞停滞在 G2/M,具有衰老细胞和有丝分裂紊乱的特征。PGV-1 和索拉非尼在下调 p-EGFR 方面表现出相同的效果,这表明这两种化合物在表皮生长因子受体活化或作为酪氨酸激酶抑制剂方面具有相同的靶点。PGV-1抑制了HuH-6和HLF细胞中MYCN的表达,但稳定了cMYC-T58,这表明即使MYCN被下调,细胞仍保持着cMYC的活性形式。在这方面,PGV-1 还能稳定 PLK-1 和 AurA 的表达:结论:与索拉非尼相比,PGV-1具有更强的细胞毒性。结论:与索拉非尼相比,PGV-1具有更强的细胞毒性,MYCN表达越低,PGV-1的细胞毒性作用越强。通过抑制表皮生长因子受体,PGV-1可抑制两种细胞在有丝分裂期的细胞周期进展,并稳定PLK-1和AurA,这与抑制MYCN表达有关。
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PGV-1 Causes Disarrangement of Spindle Microtubule Organization Resulting in Aberrant Mitosis in HLF and HuH6 Cells Associated with Altered MYCN Status.

Purpose: The HLF and HuH-6 cell lines represent hepatocellular carcinoma (HCC) with different characteristics in chromosome content that may give different drug responses. Here, PGV-1 was intended to challenge the growth-suppressing effect on HLF and HuH-6 and trace the molecular target mechanism of action compared to sorafenib.

Methods: We applied MTT cytotoxic assay, colony forming assay, flow cytometry analysis, immunofluorescence assay and western blot assay.

Results: PGV-1 exhibited cytotoxic effects on HLF and HuH-6 with IC-50 values of 1 µM and 2 µM, respectively, whereas sorafenib showed less cytotoxicity with IC-50 values of 5 µM and 8 µM respectively. PGV-1 suppressed the cell growth permanently but not for sorafenib. Sorafenib did not change the cell cycle profiles on both cells, but PGV-1 arrested the cells at G2/M with the characteristic of senescent cells and mitotic disarrangement. PGV-1 and sorafenib showed the same effect in downregulating p-EGFR, indicating that both compounds have the same target on EGFR activation or as Tyrosine kinase inhibitors. PGV-1 suppressed the MYCN expression in HuH-6 and HLF cells but stabilized cMYC-T58 indicating that even though the MYCN was downregulated, the cells maintained the active form of cMYC. In this regard, PGV-1 also stabilized the expression of PLK-1 and AurA.

Conclusion: PGV-1 elicits stronger cytotoxic properties compared to sorafenib. The lower the MYCN expression, the higher the cytotoxic effect of PGV-1. PGV-1 abrogates cell cycle progression of both cells in mitosis through EGFR inhibition and stabilizes PLK-1 and AurA in correlation with the suppression of MYCN expression.

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来源期刊
Advanced pharmaceutical bulletin
Advanced pharmaceutical bulletin PHARMACOLOGY & PHARMACY-
CiteScore
6.80
自引率
2.80%
发文量
51
审稿时长
12 weeks
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