组蛋白去乙酰化酶(HDAC)抑制剂在他莫昔芬耐药乳腺癌细胞中的基本抗癌机制。

IF 2.1 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Lingyan Wang, Yukai Xu, Chunhui Gao
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引用次数: 0

摘要

目的:乳腺癌是一种重要的女性恶性肿瘤,在全球范围内与癌症相关的死亡人数居高不下。耐药性降低了这种恶性肿瘤的治疗效果。本研究旨在探索组蛋白去乙酰化酶(HDAC)抑制剂曲司他丁 A(TSA)克服乳腺癌细胞对他莫昔芬耐药性的内在机制:模拟MCF-7乳腺癌细胞对他莫昔芬的耐药性。采用 MTT 法检测 HDAC 抑制剂和 PI3K 抑制剂对癌细胞的细胞毒性作用。跨孔试验用于评估经处理的癌细胞的侵袭和迁移。流式细胞仪检测法也用于评估处理过的癌细胞的细胞周期阶段。最后,用 Western 印迹法评估了血管内皮生长因子(VEGF)、E-钙粘蛋白、波形蛋白、磷酸化磷脂酰肌醇激酶(p-PI3k)、磷酸化蛋白激酶 B(p-AKT)和磷酸化雷帕霉素哺乳动物靶蛋白(p-mTOR)的表达:结果:结果表明,HDAC 抑制剂能显著降低癌细胞的活力、迁移和侵袭。此外,接受治疗的癌细胞在细胞周期 S 期的频率明显增加,而在 G2/M 期的频率明显下降。此外,HDAC 抑制剂还能改变 VEGF、E-cadherin、Vimentin、p-PI3k、p-AKT 和 p-mTOR 蛋白的水平。然而,与单用HDAC抑制剂相比,HDAC抑制剂联合PI3K抑制剂对癌细胞的影响更为深远:结论:HDAC抑制剂通过抑制PI3k/Akt/mTOR信号通路,抑制了乳腺癌耐药细胞的生存、侵袭、迁移和血管生成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Underlying anti-cancer mechanisms of histone deacetylase (HDAC) inhibitors in tamoxifen-resistant breast cancer cells.

Objectives: Breast cancer is an important women's malignancy with high cancer-related deaths worldwide. Drug resistance lowers the treatment efficacy in this malignancy. This study aimed to explore the underlying mechanisms of histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to overcome resistance to tamoxifen in breast cancer cells.

Materials and methods: Tamoxifen-resistance in MCF-7 breast cancer cells was simulated. MTT assay was used to detect the cytotoxic effects of HDAC inhibitor and PI3K inhibitor on the cancer cells. Trans-well assay was applied to evaluate the invasion and migration of the treated cancer cells. Flow cytometer assay was also applied to evaluate cell cycle phases in the treated cancer cells. Finally, expression of vascular endothelial growth factor (VEGF), E-cadherin, Vimentin, phosphorylated phosphatidylinositol kinase (p-PI3k), phosphorylated protein kinase B (p-AKT), and phosphorylated mammalian target protein of rapamycin (p-mTOR) was evaluated by western blotting.

Results: The obtained results indicated that HDAC inhibitor treatments significantly decreased viability, migration, and invasion in the cancer cells. Furthermore, the frequency of the treated cancer cells significantly increased in the S phase as well as significantly decreasing in the G2/M phase of the cell cycle. Moreover, HDAC inhibitor modified levels of VEGF, E-cadherin, Vimentin, p-PI3k, p-AKT, and p-mTOR proteins. However, HDAC inhibitor combined with PI3K inhibitor exerts more profound effects on the cancer cells as compared to HDAC inhibitor monotherapy.

Conclusion: HDAC inhibitors inhibited the survival of breast cancer drug-resistant cells, invasion, migration, and angiogenesis by inhibiting the PI3k/Akt/mTOR signaling pathway.

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来源期刊
Iranian Journal of Basic Medical Sciences
Iranian Journal of Basic Medical Sciences MEDICINE, RESEARCH & EXPERIMENTAL-PHARMACOLOGY & PHARMACY
CiteScore
4.00
自引率
4.50%
发文量
142
审稿时长
6-12 weeks
期刊介绍: The Iranian Journal of Basic Medical Sciences (IJBMS) is a peer-reviewed, monthly publication by Mashhad University of Medical Sciences (MUMS), Mashhad, Iran . The Journal of "IJBMS” is a modern forum for scientific communication. Data and information, useful to investigators in any discipline in basic medical sciences mainly including Anatomical Sciences, Biochemistry, Genetics, Immunology, Microbiology, Pathology, Pharmacology, Pharmaceutical Sciences, and Physiology, will be published after they have been peer reviewed. This will also include reviews and multidisciplinary research.
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