Massaro Chelsea, Thomas Jenna, Phanstiel Iv Otto
Department of Medical Education, College of Medicine, University of Central Florida, Orlando, FL 32826-3227, USA.
Med Sci (Basel). 2017 Dec 7;5(4):32. doi: 10.3390/medsci5040032.
Pancreatic cancers are currently the fourth leading cause of cancer-related death and new therapies are desperately needed. The most common pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). This report describes the development of therapies, which effectively deplete PDAC cells of their required polyamine growth factors. Of all human tissues, the pancreas has the highest level of the native polyamine spermidine. To sustain their high growth rates, PDACs have altered polyamine metabolism, which is reflected in their high intracellular polyamine levels and their upregulated import of exogenous polyamines. To understand how these cancers respond to interventions that target their specific polyamine pools, L3.6pl human pancreatic cancer cells were challenged with specific inhibitors of polyamine biosynthesis. We found that pancreatic cell lines have excess polyamine pools, which they rebalance to address deficiencies induced by inhibitors of specific steps in polyamine biosynthesis (e.g., ornithine decarboxylase (ODC), spermidine synthase (SRM), and spermine synthase (SMS)). We also discovered that combination therapies targeting ODC, SMS, and polyamine import were the most effective in reducing intracellular polyamine pools and reducing PDAC cell growth. A combination therapy containing difluoromethylornithine (DFMO, an ODC inhibitor) and a polyamine transport inhibitor (PTI) were shown to significantly deplete intracellular polyamine pools. The additional presence of an SMS inhibitor as low as 100 nM was sufficient to further potentiate the DFMO + PTI treatment.
胰腺癌目前是癌症相关死亡的第四大主要原因，因此迫切需要新的治疗方法。最常见的胰腺癌是胰腺导管腺癌（PDAC）。本报告描述了有效耗尽PDAC细胞所需多胺生长因子的治疗方法的开发。在所有人体组织中，胰腺中天然多胺亚精胺的含量最高。为了维持其高生长速率，PDAC改变了多胺代谢，这反映在其细胞内高多胺水平以及对外源多胺上调的摄取上。为了了解这些癌症如何对靶向其特定多胺池的干预措施做出反应，用多胺生物合成的特异性抑制剂对L3.6pl人胰腺癌细胞进行了挑战。我们发现胰腺细胞系具有过量的多胺池，它们会重新平衡以解决多胺生物合成中特定步骤（例如鸟氨酸脱羧酶（ODC）、亚精胺合酶（SRM）和精胺合酶（SMS））抑制剂诱导的缺陷。我们还发现，针对ODC、SMS和多胺摄取的联合疗法在减少细胞内多胺池和减少PDAC细胞生长方面最有效。含有二氟甲基鸟氨酸（DFMO，一种ODC抑制剂）和多胺转运抑制剂（PTI）的联合疗法被证明能显著耗尽细胞内多胺池。低至100 nM的SMS抑制剂的额外存在足以进一步增强DFMO + PTI治疗效果。
