Department of Medicine, Division of Endocrinology, University of Florida, Gainesville, FL, USA.
Department of Medicine, Division of Endocrinology, University of Florida and Malcom Randall VA Medical Center, Gainesville, FL, USA.
Metabolism. 2020 Sep;110:154297. doi: 10.1016/j.metabol.2020.154297. Epub 2020 Jun 18.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.
Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N,N-diethylnorspermine (DENSPM) and N,N- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.
Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.
This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.
嗜铬细胞瘤（PCCs）和副神经节瘤（PGLs）是神经内分泌肿瘤，大多为良性。大约 10%的 PCC 和多达 25%的 PGL 会发生转移疾病，对于这些患者，目前尚无有效的治疗方法。携带琥珀酸脱氢酶亚基 B（SDHB）基因突变的患者往往会发生转移疾病。我们假设活性琥珀酸脱氢酶 B 亚基的下调应该会导致细胞代谢特征的显著变化，并可能成为成功的药物靶向的弱点。
对人 hPheo1 细胞和 shRNA SDHB 敲低 hPheo1（hPheo1 SDHB KD）细胞进行代谢组学分析。对 115 个人类新鲜冷冻样本进行了额外的分析。使用 N，N-二乙基-5-氮杂-壬烷（DENSPM）和 N，N-二乙基-5-氮杂-壬烷（DESPM）处理进行了体外研究。DENSPM 的疗效在人源细胞系衍生的小鼠异种移植中进行了评估。
与野生型细胞相比，hPheo1 SDHB KD 细胞中的多胺途径成分升高。在 SDHx PCC/PGL 组织与非突变对应物相比，也观察到类似的观察结果。具体而言，精脒和精胺在 SDHx 突变的 PCC/PGL 中显着升高，hPheo1 SDHB KD 细胞中也有类似的趋势。多胺途径抑制剂 DENSPM 和 DESPM 有效抑制了体外 hPheo1 细胞的生长以及用 DENSPM 处理的异种移植小鼠的生长抑制。这些研究强烈暗示多胺途径在 PCC/PGL 的病理生理学中起作用，并为探索多胺类似物抑制剂在治疗转移性 PCC/PGL 中的作用提供了新的基础。
这项研究表明 SDHB 突变的 PCC/PGL 中多胺途径过度活跃。多胺途径抑制剂在体外和体内均能显著抑制 hPheo1 细胞的生长，并导致用 DENSPM 处理的异种移植小鼠的生长抑制。这些研究强烈表明多胺途径在 PCC/PGL 的病理生理学中起作用，并为探索多胺类似物抑制剂在治疗恶性 PCC/PGL 中的作用提供了新的基础。
