LBPO.ET01 · 实验与分子治疗 · Late-Breaking
异丹叶大黄素与FSP1抑制剂联合可抑制三阴性乳腺癌细胞进展
Combination of isorhapontigenin and FSP1 inhibitor suppresses triple negative breast cancer cell progression
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌是女性中最常被诊断的癌症，据估计2025年美国将有316,950例新发病例和42,170例死亡。在所有乳腺癌中，约15%被诊断为一种称为三阴性乳腺癌（TNBC；ER-/PR-/HER2-）的恶性亚型，这使得激素疗法无效。联合化疗是TNBC患者的标准治疗，但许多患者会出现化疗耐药，而化疗耐药占转移性癌症药物失败的90%。因此，迫切需要发现新药物和治疗选择以改善TNBC患者的预后。异丹叶大黄素（ISO）是一种源自中草药买麻藤（Gnetum Cleistostachyun）的二苯乙烯衍生物，已被证明对膀胱癌、肺癌和前列腺癌具有抗癌作用，但很少有研究在TNBC背景下探讨ISO。在本研究中，我们分别在人源和鼠源TNBC细胞系MDA-MB-231和4T1中研究了其潜在的抗癌作用。ISO以剂量依赖的方式显著抑制TNBC细胞的增殖和克隆形成能力。此外，ISO处理后细胞迁移能力显著降低，同时紧密连接标志物兼肿瘤抑制因子claudin-1的表达增加。而且，ISO处理在体外3D癌症模型中减小了TNBC球体的大小，并伴随细胞增殖标志物PCNA和Ki-67表达的降低。进一步的机制研究表明，ISO处理显著增加了铁死亡抑制蛋白1（FSP1）的蛋白表达，FSP1是近期发现的多种癌症化疗耐药的标志物。环己酰亚胺追踪实验和MG132处理证实，ISO以蛋白酶体依赖的方式稳定了FSP1蛋白的稳定性。ISO与FSP1抑制剂（iFSP1）共处理在降低TNBC细胞增殖和克隆形成方面具有显著的协同效应。总之，我们的研究表明ISO可抑制TNBC癌细胞的增殖和迁移。此外，这是首个证明ISO与iFSP1联合治疗对细胞增殖产生强效协同抑制的研究，凸显了ISO作为一种有前景的抗癌药物，并支持其与iFSP1联合作为对抗TNBC的新型治疗策略。
查看英文原文 English abstract
Breast cancer is the most frequently diagnosed cancer in women with an estimated 316,950 new cases and 42,170 deaths in the United States in 2025. Approximately 15% of all breast cancers are diagnosed as a malignant subtype known as triple negative breast cancer (TNBC; ER-/PR-/HER2-), which render hormonal therapies ineffective. Combination chemotherapy is the standard-of-care in TNBC patients, but many experience chemoresistance, which accounts for 90% of drug failures in metastatic cancers. Thus, the discovery of new drugs and treatment options is critically needed to improve TNBC patient outcomes. Isorhapontigenin (ISO) is a stilbene derivative from the Chinese herb, Gnetum Cleistostachyun, and has been shown to exert anti-cancer effects in bladder, lung, and prostate cancer, but very few studies have investigated ISO in the context of TNBC. In the present study, we investigated potential anti-cancer effects on MDA-MB-231 and 4T1, human and murine TNBC cell lines, respectively. ISO significantly inhibited the proliferation and clonogenicity of TNBC cells in a dose-dependent manner. In addition, the capacity of cell migration was significantly reduced upon ISO treatment, along with increased expression of claudin-1, a tight-junction marker and tumor-suppressor. Moreover, ISO treatment reduced the size of TNBC spheroids in vitro 3D cancer model, accompanied by decreased expression of cell proliferation markers, PCNA and Ki-67. Further mechanistic studies revealed that ISO treatment significantly increased protein expression of ferroptosis suppressor protein 1 (FSP1), a recently discovered marker of chemoresistance in many cancers. Cycloheximide chase assay and MG132 treatment confirmed that ISO stabilized FSP1 protein stability in the proteasome-dependent manner. Cotreatment of ISO with an FSP1 inhibitor (iFSP1) had significant synergistic effects in reducing TNBC cell proliferation and clonogenicity. In summary, our study demonstrates that ISO inhibits TNBC cancer cell proliferation and migration. Additionally, this is the first study demonstrating the combined treatment of ISO and iFSP1 exerts robust synergistic inhibition of cell proliferation, highlighting ISO as a promising anticancer drug and support its combination with iFSP1 as a novel therapeutic strategy against TNBC.
利益披露 Disclosure
F. Tran, None..
Y. Shteynfeld, None..
S. Tsao, None..
H. Sun, None..
W. Dai, None.