School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
Invest New Drugs. 2012 Feb;30(1):79-89. doi: 10.1007/s10637-010-9518-z. Epub 2010 Sep 1.
In spite of numerous advances, the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant and few new anti-tumor drugs have been developed. PCH4, a derivative of n-butylidenephthalide, has been investigated for its anti-tumor effects on oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anti-tumor mechanism of a potential target gene, Nur77, in OSCC cells, which can be induced by PCH4 treatment. Data show that PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells. When Nur77 translocation was blocked, the degree of tumor apoptosis caused by PCH4 was significantly inhibited (p < 0.05). Within the MAPK pathway, PCH4 only induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis (p < 0.05) and decreased PCH4-induced Nur77 expression (p < 0.05). In a xenograft animal model, administration of PCH4 also showed anti-tumor effects. We have demonstrated that OSCC cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4. These results indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy.
尽管取得了众多进展，但头颈部鳞状细胞癌的 5 年生存率仍然基本停滞不前，很少有新的抗肿瘤药物被开发出来。PCH4 是正丁烯基邻苯二甲酸酐的衍生物，已被研究用于其对口腔鳞状细胞癌（OSCC）的抗肿瘤作用。本研究旨在研究潜在靶基因 Nur77 在 OSCC 细胞中的抗肿瘤机制，该基因可被 PCH4 处理诱导。数据表明，PCH4 促进 Nur77 从细胞核易位到细胞质，并诱导 OSCC 细胞凋亡。当 Nur77 易位被阻断时，PCH4 引起的肿瘤细胞凋亡程度显著受到抑制（p<0.05）。在 MAPK 通路内，PCH4 仅诱导 JNK 磷酸化。此外，用 JNK 抑制剂处理可显著抑制 PCH4 诱导的细胞凋亡（p<0.05）并降低 PCH4 诱导的 Nur77 表达（p<0.05）。在异种移植动物模型中，给予 PCH4 也显示出抗肿瘤作用。我们已经证明 OSCC 细胞对 PCH4 敏感，并且 Nur77 蛋白从细胞核到细胞质的易位可能与 PCH4 诱导的细胞凋亡有关。这些结果表明 PCH4 可能作为一种治疗 OSCC 的潜在抗肿瘤药物。
