Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-κB downregulation.
Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-κB downregulation.
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DOI：
10.1002/ijc.28583
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发表时间：
2014-05-15
影响因子：
6.4
通讯作者：
Herr, Ingrid
中科院分区：
文献类型：
--
作者：
Liu, Li;Salnikov, Alexei V.;Bauer, Nathalie;Aleksandrowicz, Ewa;Labsch, Sabrina;Nwaeburu, Clifford;Mattern, Juergen;Gladkich, Jury;Schemmer, Peter;Werner, Jens;Herr, Ingrid
关键词：
胰腺导管腺癌（PDA）是最致命的恶性肿瘤之一，其特征在于具有低灌注区域的强烈肿瘤间质，显著的炎症反应和明显的治疗抗性。迫切需要新的治疗剂。雷公藤甲素也被称为“雷神藤”，在传统中药中用于治疗类风湿性关节炎和癌症有着悠久的历史，目前正处于第二阶段临床试验，以确定相对于安慰剂的疗效。作者通过在胰腺癌干细胞（CSC）实验模型中诱导缺氧来模拟患者肿瘤的情况，并评估雷公藤甲素的治疗效果。缺氧诱导集落和球状体形成、醛脱氢酶1（ALDH 1）和NF-κB活性、迁移潜力和形态学向成纤维细胞样表型的转变，以及干细胞和上皮-间充质转化相关蛋白表达。雷公藤内酯醇有效地抑制缺氧诱导的转录信号转导和下调上皮间质转化（EMT）和CSC功能在建立高度恶性细胞系，而敏感的癌细胞或非恶性细胞的影响较小。雷公藤内酯醇在体内抑制肿瘤的摄取和肿瘤的生长。在从患者肿瘤中分离的原代CSC中，雷公藤内酯醇下调CSC、增殖和间充质细胞的标志物沿着上调凋亡和上皮细胞的标志物。这项研究首次表明雷公藤内酯醇逆转EMT和CSC特征，因此可能上级目前治疗PDA的化疗药物。目前胰腺癌的治疗并不直接靶向肿瘤缺氧，这是侵袭性生长、早期转移和治疗抵抗的主要介质。植物源性药物雷公藤内酯醇在中医中用于治疗类风湿性关节炎和癌症有很长的历史，并在各种研究中显示出有效的治疗特性。在这里，作者首次表明雷公藤内酯醇有效抑制缺氧诱导的信号传导，导致NF-κB活性下调，上皮-间质转化，干细胞样特征。因此，雷公藤内酯醇可能上级目前的化疗药物治疗胰腺癌。
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies characterized by an intense tumor stroma with hypoperfused regions, a significant inflammatory response and pronounced therapy resistance. New therapeutic agents are urgently needed. The plant-derived agent triptolide also known as “thunder god vine” has a long history in traditional Chinese medicine for treatment of rheumatoid arthritis and cancer and is now in a clinical phase II trial for establishing the efficacy against a placebo. The authors mimicked the situation in patient tumors by induction of hypoxia in experimental models of pancreatic cancer stem cells (CSCs) and evaluated the therapeutic effect of triptolide. Hypoxia led to induction of colony and spheroid formation, aldehyde dehydrogenase 1 (ALDH1) and NF-κB activity, migratory potential and a switch in morphology to a fibroblastoid phenotype, as well as stem cell- and epithelial–mesenchymal transition-associated protein expression. Triptolide efficiently inhibited hypoxia-induced transcriptional signaling and downregulated epithelial–mesenchymal transition (EMT) and CSC features in established highly malignant cell lines, whereas sensitive cancer cells or nonmalignant cells were less affected. In vivo triptolide inhibited tumor take and tumor growth. In primary CSCs isolated from patient tumors, triptolide downregulated markers of CSCs, proliferation and mesenchymal cells along with upregulation of markers for apoptosis and epithelial cells. This study is the first to show that triptolide reverses EMT and CSC characteristics and therefore may be superior to current chemotherapeutics for treatment of PDA. Current treatment for pancreatic cancer does not directly target tumor hypoxia, a major mediator of aggressive growth, early metastasis, and therapy resistance. The plant-derived agent triptolide has a long history of use in rheumatoid arthritis and cancer in traditional Chinese medicine and has been shown to have potent therapeutic properties in a variety of studies. Here, the authors show for the first time that triptolide effectively inhibits hypoxia-induced signaling, leading to downregulation of NF-κB activity, epithelial-mesenchymal transition, and stem cell-like features. Triptolide may therefore be superior to current chemotherapeutics for treatment of pancreatic cancer.
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