木犀草素增强PX-478在转移性乳腺癌细胞缺氧反应中的抗癌作用。

IF 3 4区 医学 Q3 CHEMISTRY, MEDICINAL
Muzaffer Dukel, Fatema Zarzou
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引用次数: 0

摘要

重度缺氧应激的存在可以通过缺氧诱导因子1- α (HIF-1α)的上调来驱动肿瘤生长、血管生成和转移特征。因此,靶向HIF-1α被认为是一种很有前途的策略,因为HIF-1α活性的增加是恶性肿瘤侵袭性表型的关键因素。在这项研究中,我们旨在研究几种黄酮类化合物(单独或与PX-478联合)对乳腺癌细胞株的抗癌作用。方法:采用细胞活力法检测木犀草素和PX-478单独或联合使用对缺氧条件下乳腺癌细胞HIF-1α水平的影响。为了确定木犀草素+PX-478联合抑制细胞生长的基本原理,我们进行了常氧和缺氧条件下细胞存活、凋亡、细胞周期、侵袭和迁移的实验。此外,我们通过彗星试验和免疫荧光染色评估了这种组合对缺氧应激下DNA损伤反应的影响。结果:木犀草素+PX-478联合用药可显著抑制MDA-MB-231细胞的生长。此外,我们评估了MDA-MB-231细胞中HIF-1α的时间依赖性表达,发现木犀草素和PX-478联合使用可下调HIF-1α水平。最后,我们发现木犀草素+PX-478联合使用可诱导细胞凋亡和G2细胞周期阻滞,并增强DNA损伤反应。这种组合也使乳腺癌细胞对缺氧应激下的电离辐射敏感。讨论:研究结果表明,木犀草素和PX-478联合靶向HIF-1α可能提供一种协同方法来抑制肿瘤生长并增强缺氧条件下的治疗反应。观察到的对细胞凋亡、细胞周期阻滞和DNA损伤反应的影响表明,这种组合可能是克服缺氧诱导的乳腺癌治疗抵抗的有希望的策略。结论:木犀草素与PX-478联用可通过抑制乳腺癌细胞生长和诱导缺氧条件下的DNA损伤反应,增强PX-478对乳腺癌细胞的抗癌作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Luteolin Enhances Anticancer Effects of PX-478 during Hypoxic Response in Metastatic Breast Cancer Cells.

Introduction: The presence of severe hypoxic stress can drive tumor growth, angiogenesis, and metastatic characteristics via up-regulated hypoxia-inducible factor 1-alpha (HIF-1α). Hence, targeting HIF-1α is considered a promising strategy, as increased HIF-1α activity is a key factor in the aggressive phenotype of malignancies. In this study, we aimed to investigate the anti-cancer effects of several flavonoids, both single and in combination with PX-478, in breast cancer cell lines.

Methods: We tested the effects of luteolin and PX-478, both alone and in combination, on HIF-1α level in breast cancer cells under hypoxia using the cell viability assay. To determine the rationale for the cell growth inhibition induced by the luteolin+PX-478 combination, we conducted experiments to assess cell survival, apoptosis, cell cycle, invasion, and migration under both normoxic and hypoxic conditions. Furthermore, we evaluated the effect of this combination on DNA damage response under hypoxic stress via Comet assay and immunofluorescence staining.

Results: Our findings revealed that the luteolin+PX-478 combination significantly suppressed the growth of MDA-MB-231 cells. In addition, we assessed time-dependent expression of HIF1α in MDA-MB-231 cells and observed that the combination of luteolin and PX-478 down-regulated the HIF-1α level. Finally, we found that the luteolin+PX-478 combination induced apoptosis and G2 cell cycle arrest and enhanced DNA damage response. This combination also sensitized breast cancer cells to ionizing radiation in hypoxic stress.

Discussion: The findings suggested that targeting HIF-1α with a combination of luteolin and PX-478 may provide a synergistic approach to suppressing tumor growth and enhancing therapeutic response under hypoxic conditions. The observed effects on apoptosis, cell cycle arrest, and DNA damage response indicated that this combination could be a promising strategy for overcoming hypoxia-induced resistance in breast cancer therapy.

Conclusion: Collectively, our results suggested the combination of luteolin and PX-478 to enhance the anticancer effects of PX-478 in breast carcinoma cells by impeding the cell growth and inducing DNA damage response under hypoxia.

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来源期刊
Anti-cancer agents in medicinal chemistry
Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL
CiteScore
5.10
自引率
3.60%
发文量
323
审稿时长
4-8 weeks
期刊介绍: Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.
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