{"title":"荔枝籽总黄酮通过调控PI3K/AKT/mTOR和MAPKs信号通路抑制乳腺癌转移。","authors":"Xin Yang, Shoushi Liu, Ying Liu, Yuanshuo Wang, Dianxin Cui, Taijin Lan, Dan Zhu, Zhiheng Su, Erwei Hao, Lilan Qin, Hongwei Guo","doi":"10.1080/13880209.2025.2488135","DOIUrl":null,"url":null,"abstract":"<p><strong>Context: </strong>Total flavonoids from <i>Litchi chinensis</i> Sonn. (Sapindaceae) seeds (TFLS) effectively attenuate stem cell-like properties in breast cancer cells. However, their pharmacological effects and mechanisms in suppressing breast cancer metastasis remain unclear.</p><p><strong>Objective: </strong>This study aimed to elucidate the inhibitory effects and underlying mechanisms of TFLS on breast cancer metastasis.</p><p><strong>Materials and methods: </strong>The antiproliferative, migratory, and invasive activities of breast cancer cells following TFLS treatment were evaluated using CCK-8, wound-healing, and transwell assays. The epithelial-mesenchymal transition (EMT) biomarkers were evaluated <i>via</i> Western blot analysis. The anti-metastatic effects of TFLS were further validated <i>in vivo</i> using zebrafish and mouse models. Network pharmacology methodology was utilized to predict potential targets and signaling pathways, which were subsequently corroborated by Western blot. Potential active compounds were identified through molecular docking, and the chemical constituents of TFLS were analyzed and characterized using UPLC-QTOF/MS.</p><p><strong>Results: </strong>TFLS suppressed the proliferation of MDA-MB-231 and MDA-MB-468 cells, with IC<sub>50</sub> values of 44.47 μg/mL and 37.35 μg/mL at 72 h, respectively. It effectively suppressed breast cancer metastasis <i>in vitro</i>, demonstrated by a marked reduction in cellular motility and invasiveness, alongside the reversal of EMT. Consistent with pathway enrichment analysis, network pharmacology revealed that TFLS reduced the phosphorylation levels of PI3K, AKT, mTOR, JNK, ERK, and p38 in breast cancer cells. Molecular docking identified seven potential active ingredients, and UPLC-MS/MS confirmed the presence of key compounds, including procyanidin A2.</p><p><strong>Discussion and conclusion: </strong>TFLS effectively inhibits breast cancer cell proliferation, migration, and invasion <i>in vitro</i> by reversing the EMT phenotype, while suppressing metastasis <i>in vivo</i>. These effects are likely mediated <i>via</i> the attenuation of the PI3K/AKT/mTOR and MAPK signaling pathways.</p>","PeriodicalId":19942,"journal":{"name":"Pharmaceutical Biology","volume":"63 1","pages":"229-249"},"PeriodicalIF":3.9000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001861/pdf/","citationCount":"0","resultStr":"{\"title\":\"Total flavonoids of litchi seed inhibit breast cancer metastasis by regulating the PI3K/AKT/mTOR and MAPKs signaling pathways.\",\"authors\":\"Xin Yang, Shoushi Liu, Ying Liu, Yuanshuo Wang, Dianxin Cui, Taijin Lan, Dan Zhu, Zhiheng Su, Erwei Hao, Lilan Qin, Hongwei Guo\",\"doi\":\"10.1080/13880209.2025.2488135\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Context: </strong>Total flavonoids from <i>Litchi chinensis</i> Sonn. (Sapindaceae) seeds (TFLS) effectively attenuate stem cell-like properties in breast cancer cells. However, their pharmacological effects and mechanisms in suppressing breast cancer metastasis remain unclear.</p><p><strong>Objective: </strong>This study aimed to elucidate the inhibitory effects and underlying mechanisms of TFLS on breast cancer metastasis.</p><p><strong>Materials and methods: </strong>The antiproliferative, migratory, and invasive activities of breast cancer cells following TFLS treatment were evaluated using CCK-8, wound-healing, and transwell assays. The epithelial-mesenchymal transition (EMT) biomarkers were evaluated <i>via</i> Western blot analysis. The anti-metastatic effects of TFLS were further validated <i>in vivo</i> using zebrafish and mouse models. Network pharmacology methodology was utilized to predict potential targets and signaling pathways, which were subsequently corroborated by Western blot. Potential active compounds were identified through molecular docking, and the chemical constituents of TFLS were analyzed and characterized using UPLC-QTOF/MS.</p><p><strong>Results: </strong>TFLS suppressed the proliferation of MDA-MB-231 and MDA-MB-468 cells, with IC<sub>50</sub> values of 44.47 μg/mL and 37.35 μg/mL at 72 h, respectively. It effectively suppressed breast cancer metastasis <i>in vitro</i>, demonstrated by a marked reduction in cellular motility and invasiveness, alongside the reversal of EMT. Consistent with pathway enrichment analysis, network pharmacology revealed that TFLS reduced the phosphorylation levels of PI3K, AKT, mTOR, JNK, ERK, and p38 in breast cancer cells. Molecular docking identified seven potential active ingredients, and UPLC-MS/MS confirmed the presence of key compounds, including procyanidin A2.</p><p><strong>Discussion and conclusion: </strong>TFLS effectively inhibits breast cancer cell proliferation, migration, and invasion <i>in vitro</i> by reversing the EMT phenotype, while suppressing metastasis <i>in vivo</i>. These effects are likely mediated <i>via</i> the attenuation of the PI3K/AKT/mTOR and MAPK signaling pathways.</p>\",\"PeriodicalId\":19942,\"journal\":{\"name\":\"Pharmaceutical Biology\",\"volume\":\"63 1\",\"pages\":\"229-249\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2025-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001861/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmaceutical Biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/13880209.2025.2488135\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/15 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICAL LABORATORY TECHNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutical Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/13880209.2025.2488135","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICAL LABORATORY TECHNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：荔枝总黄酮。（Sapindaceae）种子（TFLS）能有效削弱乳腺癌细胞的干细胞样特性。然而，其抑制乳腺癌转移的药理作用和机制尚不清楚。目的：探讨TFLS对乳腺癌转移的抑制作用及其机制。材料和方法：采用CCK-8、伤口愈合和transwell试验评估TFLS治疗后乳腺癌细胞的抗增殖、迁移和侵袭活性。Western blot分析上皮-间质转化（EMT）生物标志物。通过斑马鱼和小鼠模型进一步验证了TFLS的抗转移作用。使用网络药理学方法预测潜在靶点和信号通路，随后通过Western blot证实。通过分子对接鉴定了潜在活性化合物，并利用UPLC-QTOF/MS对TFLS的化学成分进行了分析和表征。结果：TFLS对MDA-MB-231和MDA-MB-468细胞的增殖有抑制作用，72 h IC50值分别为44.47 μg/mL和37.35 μg/mL。它在体外有效地抑制乳腺癌转移，证明了细胞活力和侵袭性的显著降低，以及EMT的逆转。与通路富集分析一致，网络药理学显示TFLS降低了乳腺癌细胞中PI3K、AKT、mTOR、JNK、ERK和p38的磷酸化水平。分子对接鉴定出7种潜在的活性成分，UPLC-MS/MS确认了关键化合物的存在，包括原花青素A2。讨论与结论：TFLS通过逆转EMT表型，在体外有效抑制乳腺癌细胞的增殖、迁移和侵袭，同时在体内抑制转移。这些影响可能是通过PI3K/AKT/mTOR和MAPK信号通路的衰减介导的。
Total flavonoids of litchi seed inhibit breast cancer metastasis by regulating the PI3K/AKT/mTOR and MAPKs signaling pathways.
Context: Total flavonoids from Litchi chinensis Sonn. (Sapindaceae) seeds (TFLS) effectively attenuate stem cell-like properties in breast cancer cells. However, their pharmacological effects and mechanisms in suppressing breast cancer metastasis remain unclear.
Objective: This study aimed to elucidate the inhibitory effects and underlying mechanisms of TFLS on breast cancer metastasis.
Materials and methods: The antiproliferative, migratory, and invasive activities of breast cancer cells following TFLS treatment were evaluated using CCK-8, wound-healing, and transwell assays. The epithelial-mesenchymal transition (EMT) biomarkers were evaluated via Western blot analysis. The anti-metastatic effects of TFLS were further validated in vivo using zebrafish and mouse models. Network pharmacology methodology was utilized to predict potential targets and signaling pathways, which were subsequently corroborated by Western blot. Potential active compounds were identified through molecular docking, and the chemical constituents of TFLS were analyzed and characterized using UPLC-QTOF/MS.
Results: TFLS suppressed the proliferation of MDA-MB-231 and MDA-MB-468 cells, with IC50 values of 44.47 μg/mL and 37.35 μg/mL at 72 h, respectively. It effectively suppressed breast cancer metastasis in vitro, demonstrated by a marked reduction in cellular motility and invasiveness, alongside the reversal of EMT. Consistent with pathway enrichment analysis, network pharmacology revealed that TFLS reduced the phosphorylation levels of PI3K, AKT, mTOR, JNK, ERK, and p38 in breast cancer cells. Molecular docking identified seven potential active ingredients, and UPLC-MS/MS confirmed the presence of key compounds, including procyanidin A2.
Discussion and conclusion: TFLS effectively inhibits breast cancer cell proliferation, migration, and invasion in vitro by reversing the EMT phenotype, while suppressing metastasis in vivo. These effects are likely mediated via the attenuation of the PI3K/AKT/mTOR and MAPK signaling pathways.
期刊介绍：
Pharmaceutical Biology will publish manuscripts describing the discovery, methods for discovery, description, analysis characterization, and production/isolation (including sources and surveys) of biologically-active chemicals or other substances, drugs, pharmaceutical products, or preparations utilized in systems of traditional medicine.
Topics may generally encompass any facet of natural product research related to pharmaceutical biology. Papers dealing with agents or topics related to natural product drugs are also appropriate (e.g., semi-synthetic derivatives). Manuscripts will be published as reviews, perspectives, regular research articles, and short communications. The primary criteria for acceptance and publication are scientific rigor and potential to advance the field.
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