Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Cancer. 2012 Nov 15;131(10):2445-55. doi: 10.1002/ijc.27524. Epub 2012 Aug 20.
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in this study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter (NET) system, considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was performed on three different stable PHEO cell lines. We found that blocking NF-κB with TTL or capsaicin increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, in vivo treatment with TTL significantly reduced metastatic burden in an animal model of metastatic PHEO. The present study for the first time shows how NF-κB inhibitors could be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis.
嗜铬细胞瘤（pheochromocytomas，PHEOs）和副神经节瘤（paragangliomas，PGLs）是分别起源于肾上腺髓质或交感/副交感副神经节的特定类型的神经内分泌肿瘤。尽管这些肿瘤受到了深入研究，但尚未建立针对转移性 PHEO 或 PGL 的非常有效的治疗方法。非常需要对这些肿瘤的新型治疗方法进行临床前评估。因此，在这项研究中，我们测试了雷公藤红素（triptolide，TTL）的效果，TTL 是一种有效的核因子-κB（nuclear factor-kappaB，NF-κB）抑制剂，对细胞膜去甲肾上腺素转运体（norepinephrine transporter，NET）系统有影响，NET 系统被认为是放射性药物 131I-间碘苄胍（131I-metaiodobenzylguanidine，131I-MIBG）的“守门员”。我们测量了 NET 的 mRNA 和蛋白水平的变化，并将其与促凋亡因子和转移抑制相关联。这项研究在三种不同的稳定 PHEO 细胞系上进行。我们发现，用 TTL 或辣椒素阻断 NF-κB 既增加了 NET 的 mRNA 水平又增加了其蛋白水平。通过该位点的 mRNA 沉默以及使用 NF-κB 抗肽来验证 NF-κB 对 NET 上调的参与。此外，体内用 TTL 治疗在转移性 PHEO 的动物模型中显著降低了转移负担。本研究首次表明，NF-κB 抑制剂如何通过显著上调 NET 来增加 131I-MIBG 的疗效并诱导细胞凋亡，从而成功用于治疗转移性 PHEO/PGL。
