神经母细胞瘤(NB) 和嗜铬细胞瘤/副神经节瘤(PHEO/PGL) 是神经内分泌肿瘤。注射放射性标记的间位碘苄胍 (mIBG) 后，通过闪烁显像技术可以对这些肿瘤进行成像，mIBG是一种被肿瘤细胞通过单胺转运体吸收的去甲肾上腺素类似物。诱导这些转运体的药物处理是改善这些肿瘤成像和治疗 (治疗诊断联合应用) 的有希望的方法。通过使用转染的人类胚胎肾细胞(HEK)，可以鉴定介导mIBG内化的转运体。通过在细胞系中测试组蛋白去乙酰化酶抑制剂(HDACi)和PI3K/AKT/mTOR通路抑制剂的作用，评估其对mIBG内化的影响。通过对人源移植小鼠进行研究，评估最有前景的HDACi对123I-mIBG摄取的影响。 转染的HEK细胞表明去甲肾上腺素和多巴胺转运体(NET和DAT)主动内化mIBG。钠苯丁酸(一种HDACi)、CUDC-907(双重HDACi和PI3K抑制剂)、BGT226(PI3K抑制剂)、VS-5584和拉帕霉素 (mTOR的两种抑制剂)分别与未经处理的细胞相比，将一个神经母细胞瘤细胞系(IGR-NB8)中的mIBG内化增加了2.9倍、2.1倍、2.5倍、1.5倍和1.3倍。CUDC-907还增加了其他两个NB细胞系和一个PHEO细胞系中的mIBG内化。我们证明，mIBG的内化主要通过NET进行。在带有IGR-NB8细胞的移植小鼠中，口服5mg/kg的CUDC-907治疗后，123I-mIBG在注射后4小时和24小时分别增加了2.3倍和1.9倍，与未经处理的组相比。 CUDC-907通过上调NET在体外和体内促进了mIBG的内化。© 2023. BioMed Central Ltd., Springer Nature的一部分。

Neuroblastoma (NB) and pheochromocytoma/paraganglioma (PHEO/PGL) are neuroendocrine tumors. Imaging of these neoplasms is performed by scintigraphy after injection of radiolabeled meta-iodobenzylguanidine (mIBG), a norepinephrine analog taken up by tumoral cells through monoamine transporters. The pharmacological induction of these transporters is a promising approach to improve the imaging and therapy (theranostics) of these tumors.Transporters involved in mIBG internalization were identified by using transfected Human Embryonic Kidney (HEK) cells. Histone deacetylase inhibitors (HDACi) and inhibitors of the PI3K/AKT/mTOR pathway were tested in cell lines to study their effect on mIBG internalization. Studies in xenografted mice were performed to assess the effect of the most promising HDACi on 123I-mIBG uptake.Transfected HEK cells demonstrated that the norepinephrine and dopamine transporter (NET and DAT) avidly internalizes mIBG. Sodium-4-phenylbutyrate (an HDACi), CUDC-907 (a dual HDACi and PI3K inhibitor), BGT226 (a PI3K inhibitor) and VS-5584 and rapamycin (two inhibitors of mTOR) increased mIBG internalization in a neuroblastoma cell line (IGR-NB8) by 2.9-, 2.1-, 2.5-, 1.5- and 1.3-fold, respectively, compared with untreated cells. CUDC-907 also increased mIBG internalization in two other NB cell lines and in one PHEO cell line. We demonstrated that mIBG internalization occurs primarily through the NET. In xenografted mice with IGR-NB8 cells, oral treatment with 5 mg/kg of CUDC-907 increased the tumor uptake of 123I-mIBG by 2.3- and 1.9-fold at 4 and 24 h post-injection, respectively, compared to the untreated group.Upregulation of the NET by CUDC-907 lead to a better internalization of mIBG in vitro and in vivo.© 2023. BioMed Central Ltd., part of Springer Nature.