A herbal pair of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang induced ferroptosis in ovarian cancer A2780 cells via inducing heme catabolism and ferritinophagy.
Zhen Wang, Min Liu, Guang-Xing Li, Liu Zhang, Kai-Yue Ding, Si-Qi Li, Bing-Qing Gao, Peng Chen, Hyok-Chol Choe, Lun-Yue Xia, Yu-Tong Yang, Yi Liu, Xue Sui, Jun-Nan Ma, Lin Zhang
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引用次数: 0
Abstract
Objective: Despite the combination of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) being a recognized Chinese medicinal herbal pair that is commonly used in the treatment of ovarian cancer, there is a poor understanding of their pharmacological mechanisms. This study examines the antitumor properties and potential mechanisms of SB-SD on human ovarian cancer A2780 cells through a multi-omics approach, establishing a pharmacological basis for clinical utilization.
Methods: A range of mass ratios and reagents were used in the hot reflux extraction of SB-SD. The inhibitory effect of the SB-SD extracts on A2780 cell proliferation was assessed using the cell-counting kit 8 assay. A zebrafish tumor implantation model was used to evaluate the effects of SB-SD extracts on tumor growth and metastasis in vivo. Transcriptomics and proteomics were used to investigate alterations in biological pathways in A2780 cells after treatment with different concentrations of SB-SD extract. Cell cycle, cell apoptosis, intracellular free iron concentration, intracellular reactive oxygen species (ROS) concentration, malondialdehyde (MDA), and mitochondrial membrane potential were measured. Real-time quantitative reverse transcription polymerase chain reaction and Western blotting were utilized to investigate the effects of heme catabolism and ferritinophagy on ferroptosis induced by SB-SD extract in A2780 cells.
Results: The 70% ethanol extract of SB-SD (a mass ratio of 4:1) inhibited A2780 cell proliferation significantly with a half maximal inhibitory concentration of 660 μg/mL in a concentration- and time-dependent manner. Moreover, it effectively suppressed tumor growth and metastasis in a zebrafish tumor implantation model. SB-SD extract induced the accumulation of free iron, ROS, MDA, and mitochondrial damage in A2780 cells. The mechanisms might involve the upregulated expression of ferritinophagy-related genes microtubule-associated protein 1 light chain 3, autophagy-related gene 5, and nuclear receptor coactivator 4.
Conclusion: SB-SD extract effectively inhibited the development of ovarian cancer both in vitro and in vivo. Its mechanism of action involved inducing ferroptosis by facilitating heme catabolism and ferritinophagy. This herbal pair holds promise as a potential therapeutic option for ovarian cancer treatment and may be utilized in combination with routine treatment to improve the treatment outcomes of ovarian cancer patients. Please cite this article as: Wang Z, Liu M, Li GX, Zhang L, Ding KY, Li SQ, Gao BQ, Chen P, Choe HC, Xia LY, Yang YT, Liu Y, Sui X, Ma JN, Zhang L. A herbal pair of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang induced ferroptosis in ovarian cancer A2780 cells via inducing heme catabolism and ferritinophagy. J Integr Med. 2024; Epub ahead of print.
Scutellaria barbata D. Don和Scleromitrion diffusum（Willd.）
目的：尽管黄芩(Scutellaria barbata D. Don)和白花蛇舌草(Scleromitrion diffusum (Willd.) R.J. Wang)(SB-SD)是公认的中药组合，常用于治疗卵巢癌，但人们对其药理机制了解甚少。本研究通过多组学方法研究 SB-SD 对人类卵巢癌 A2780 细胞的抗肿瘤特性和潜在机制，为临床应用建立药理基础：方法：在热回流提取SB-SD过程中使用了不同的质量比和试剂。采用细胞计数试剂盒 8 方法评估了 SB-SD 提取物对 A2780 细胞增殖的抑制作用。斑马鱼肿瘤植入模型用于评估 SB-SD 提取物对体内肿瘤生长和转移的影响。转录组学和蛋白质组学用于研究不同浓度的 SB-SD 提取物处理 A2780 细胞后生物通路的改变。研究测定了细胞周期、细胞凋亡、细胞内游离铁浓度、细胞内活性氧（ROS）浓度、丙二醛（MDA）和线粒体膜电位。利用实时定量反转录聚合酶链反应和 Western 印迹技术研究了血红素分解和铁蛋白吞噬对 SB-SD 提取物诱导的 A2780 细胞铁变态反应的影响：SB-SD的70%乙醇提取物（质量比为4:1）能显著抑制A2780细胞的增殖，半数最大抑制浓度为660 μg/mL，且呈浓度和时间依赖性。此外，它还能在斑马鱼肿瘤植入模型中有效抑制肿瘤的生长和转移。SB-SD 提取物能诱导 A2780 细胞中游离铁、ROS、MDA 的积累和线粒体损伤。其机制可能涉及铁蛋白吞噬相关基因微管相关蛋白 1 轻链 3、自体吞噬相关基因 5 和核受体辅激活因子 4 的表达上调：SB-SD提取物能有效抑制卵巢癌的体内外发展。其作用机制包括通过促进血红素分解和噬铁蛋白诱导铁变态反应。这对草药有望成为卵巢癌治疗的潜在疗法，并可与常规治疗相结合，改善卵巢癌患者的治疗效果。本文引用如前：Wang Z, Liu M, Li GX, Zhang L, Ding KY, Li SQ, Gao BQ, Chen P, Choe HC, Xia LY, Yang YT, Liu Y, Sui X, Ma JN, Zhang L. A herbal pair of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang induced ferroptosis in ovarian cancer A2780 cells via inducing heme catabolism and ferritinophagy.J Integr Med.2024; Epub ahead of print.
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