查耳酮-9:对三阴性乳腺癌细胞具有强效抗癌作用的新型 JAK-STAT 通路抑制剂。

IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Song-Hee Lee, Haeri Lee, Yong-Jin Kwon, Seul-Ki Kim, Eun-Bi Seo, Jie Ohn Sohn, Byung-Hak Kim, Jung-Youl Park, Sang-Kyu Ye
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引用次数: 0

摘要

背景:乳腺癌仍然是全球女性癌症发病率和死亡率的主要原因,三阴性乳腺癌(TNBC)带来了重大的治疗挑战。Janus激酶/信号转导和转录激活因子(JAK/STAT)通路的失调有助于肿瘤的进展,使其成为潜在的治疗靶点。查尔酮因其多种生物活性而闻名,包括抗癌作用,有望用于药物开发。本研究探讨了新型查尔酮衍生物(E)-4-(3-(2-(苯氧基)-6-羟基苯基)-3-氧丙基-1-烯-1-基)苯甲酸(查尔酮-9)的抗癌活性。方法:研究查尔酮-9对乳腺癌细胞系MDA-MB-231和MDA-MB-468的细胞毒作用。采用Western blotting和qRT-PCR分析对JAK1、JAK2、STAT1和STAT3活化及其下游基因表达的影响。通过硅分子对接分析确定查尔酮-9是否能与JAK1和JAK2相互作用。采用创面愈合实验观察查尔酮-9对肿瘤细胞迁移的影响,采用流式细胞术分析查尔酮-9是否抑制肿瘤细胞周期进展和诱导细胞凋亡。同时检测细胞凋亡标志物的表达。结果:查尔酮-9在乳腺癌细胞系中表现出剂量依赖性的细胞毒性,TNBC细胞表现出更高的敏感性。查尔酮-9有效抑制JAK1、JAK2、STAT1和STAT3的激活,优于传统的JAK/STAT抑制剂。查尔酮-9的结构被证实能稳定地与JAK1和JAK2蛋白相互作用。它还抑制STAT1和STAT3靶基因的表达,减少肿瘤细胞的迁移,诱导细胞凋亡,PARP和caspase的裂解和survivin水平的降低证明了这一点。结论:查尔酮-9具有显著的抗癌活性,特别是对TNBC。通过靶向JAK/STAT通路并促进细胞凋亡,查尔酮-9成为治疗侵袭性乳腺癌的有希望的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Chalcone-9: a novel inhibitor of the JAK-STAT pathway with potent anti-cancer effects in triple-negative breast cancer cells.

Background: Breast cancer remains the leading cause of cancer incidence and mortality among women worldwide, with triple-negative breast cancer (TNBC) posing significant treatment challenges. The dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway contributes to tumor progression, making it a potential therapeutic target. Chalcones, known for their diverse biological activities, including anti-cancer effects, hold promise for drug development. This study explores the anti-cancer activity of (E)-4-(3-(2-(benzyloxy)-6-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoic acid (chalcone-9), a novel chalcone derivative.

Methods: The cytotoxic effects of chalcone-9 were evaluated in breast cancer cell lines, including TNBC lines MDA-MB-231 and MDA-MB-468. Western blotting and qRT-PCR were used to analyze the impact on JAK1, JAK2, STAT1, and STAT3 activation and their downstream gene expression. In silico molecular docking analysis was conducted to determine whether chalcone-9 can interact with JAK1 and JAK2. A wound healing assay was used to observe the effect of chalcone-9 on tumor cell migration, and flow cytometry was employed to analyze whether chalcone-9 inhibits tumor cell cycle progression and induces apoptosis. The expression of apoptosis markers was also assessed.

Results: Chalcone-9 exhibited dose-dependent cytotoxicity in breast cancer cell lines, with TNBC cells showing higher sensitivity. Chalcone-9 effectively inhibited the activation of JAK1, JAK2, STAT1, and STAT3, outperforming conventional JAK/STAT inhibitors. The structure of chalcone-9 was confirmed to stably interact with JAK1 and JAK2 proteins. It also suppressed STAT1 and STAT3 target gene expression, reduced tumor cell migration, and induced apoptosis, as evidenced by PARP and caspase cleavage and decreased survivin levels.

Conclusions: Chalcone-9 demonstrates significant anti-cancer activity, particularly against TNBC. By targeting the JAK/STAT pathway and promoting apoptosis, chalcone-9 emerges as a promising therapeutic candidate for aggressive breast cancers.

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来源期刊
Pharmacological Reports
Pharmacological Reports 医学-药学
CiteScore
8.40
自引率
0.00%
发文量
91
审稿时长
6 months
期刊介绍: Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.
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