Zheng Hongxia, Gao Yue, Ye Mujie, Bai Jianan, Liu Min, Long Qin, Chen Jinhao, Qiang Xinyun, Tang Qiyun
Department of Neuroendocrine Tumor, Jiangsu Province Hospital, The First Affiliated Hospital with Nanjing Medical University, Institute of Neuroendocrine Tumor of Nanjing Medical University, Institute of Neuroendocrine Tumor of Collaborative Innovation Center for Cancer Personalized Medicine of Jiangsu Province, Neuroendocrine Tumor Diagnosis and Treatment Center of Jiangsu Province, Nanjing, China.
Transl Cancer Res. 2025 Aug 31;14(8):4586-4597. doi: 10.21037/tcr-2024-2424. Epub 2025 Aug 13.
Pancreatic neuroendocrine neoplasms (pNENs) represent a rare group of highly heterogeneous tumors derived from pancreatic epithelial cells exhibiting neuroendocrine differentiation properties. Everolimus, an oral inhibitor of mTOR, is the most promising drug for patients with unresectable, metastatic disease, particularly in progressive well-differentiated pNENs. Sorafenib is utilized in the treatment of hepatocellular carcinoma (HCC), renal cell carcinoma, and differentiated thyroid cancer. Furthermore, it plays an indispensable role in the management of multisystem malignancies. This study aims to investigate the effects and mechanisms of sorafenib, as well as its potential for combination use with everolimus in pNENs.
QGP-1and BON-1cells were collected from routine culture and treated with various concentrations of sorafenib, everolimus, and dual-drug combinations for 24 hours. The capacity of these medications to influence tumor activity was evaluated through the use of the Cell Counting Kit-8 (CCK-8) assay, cloning assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, transwell assay, and analysis of the xenograft tumor model. Western blot analysis was conducted to detect the level of mTOR in QGP-1 and BON-1 cells.
Compared to the control group, the proliferation and migration of sorafenib-treated cells were significantly inhibited. Furthermore, as drug concentration increased, the proliferation rates of both cell types decreased. Notably, the inhibition of cell proliferation was more pronounced in the sorafenib and everolimus combination group than in the single-drug group. Western blot results indicated that the expression level of mTOR was down-regulated in the experimental group after treatment with sorafenib, everolimus, and the dual-drug combination for 24 hours, compared to the control group. In experiments involving animals, tumors in the groups treated with both high and low doses of sorafenib were smaller than those observed in the control group, and liver metastasis was suppressed in the experimental groups when compared to the control.
Sorafenib can inhibit the proliferation and migration of pNENs by down-regulating the mTOR pathway. The combination of sorafenib and everolimus exhibits a stronger anti-tumor effect.
胰腺神经内分泌肿瘤（pNENs）是一组罕见的、高度异质性的肿瘤，起源于具有神经内分泌分化特性的胰腺上皮细胞。依维莫司是一种口服的mTOR抑制剂，是不可切除的转移性疾病患者最有前景的药物，尤其是在进展期高分化pNENs患者中。索拉非尼用于治疗肝细胞癌（HCC）、肾细胞癌和分化型甲状腺癌。此外，它在多系统恶性肿瘤的治疗中发挥着不可或缺的作用。本研究旨在探讨索拉非尼的作用效果及机制，以及其与依维莫司联合应用于pNENs的潜力。
从常规培养中收集QGP-1和BON-1细胞，并用不同浓度的索拉非尼、依维莫司及双药组合处理24小时。通过使用细胞计数试剂盒-8（CCK-8）检测法、克隆检测法、5-乙炔基-2'-脱氧尿苷（EdU）检测法、transwell检测法以及异种移植肿瘤模型分析来评估这些药物影响肿瘤活性的能力。进行蛋白质免疫印迹分析以检测QGP-1和BON-1细胞中mTOR的水平。
与对照组相比，索拉非尼处理的细胞的增殖和迁移受到显著抑制。此外，随着药物浓度增加，两种细胞类型的增殖率均下降。值得注意的是，索拉非尼与依维莫司联合组对细胞增殖的抑制作用比单药组更明显。蛋白质免疫印迹结果表明，与对照组相比，用索拉非尼、依维莫司及双药组合处理24小时后的实验组中mTOR的表达水平下调。在动物实验中，高剂量和低剂量索拉非尼处理组的肿瘤均小于对照组，且与对照组相比，实验组的肝转移受到抑制。
索拉非尼可通过下调mTOR通路抑制pNENs的增殖和迁移。索拉非尼与依维莫司联合表现出更强的抗肿瘤作用。
