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Med. Sci. 2017, 5(4), 32; doi:10.3390/medsci5040032

Investigation of Polyamine Metabolism and Homeostasis in Pancreatic Cancers

Department of Medical Education, College of Medicine, University of Central Florida, Orlando, FL 32826-3227, USA
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Received: 7 November 2017 / Revised: 4 December 2017 / Accepted: 5 December 2017 / Published: 7 December 2017
(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)
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Abstract

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. View Full-Text
Keywords: polyamine; cancer; metabolism; difluoromethylornithine; polyamine transport inhibitor; pancreatic ductal adenocarcinoma polyamine; cancer; metabolism; difluoromethylornithine; polyamine transport inhibitor; pancreatic ductal adenocarcinoma
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Massaro, C.; Thomas, J.; Phanstiel, O., IV. Investigation of Polyamine Metabolism and Homeostasis in Pancreatic Cancers. Med. Sci. 2017, 5, 32.

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