Evaluation of Polyamine Transport Inhibitors in a Drosophila Epithelial Model Suggests the Existence of Multiple Transport Systems.

Minpei Wang,Laurence Von Kalm,Otto Phanstiel

doi:10.3390/medsci5040027

Minpei Wang, Laurence Von Kalm + Show 1 more

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https://doi.org/10.3390/medsci5040027

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Abstract

Increased polyamine biosynthesis activity and an active polyamine transport system are characteristics of many cancer cell lines and polyamine depletion has been shown to be a viable anticancer strategy. Polyamine levels can be depleted by difluoromethylornithine (DFMO), an inhibitor of the key polyamine biosynthesis enzyme ornithine decarboxylase (ODC). However, malignant cells frequently circumvent DFMO therapy by up-regulating polyamine import. Therefore, there is a need to develop compounds that inhibit polyamine transport. Collectively, DFMO and a polyamine transport inhibitor (PTI) provide the basis for a combination therapy leading to effective intracellular polyamine depletion. We have previously shown that the pattern of uptake of a series of polyamine analogues in a Drosophila model epithelium shares many characteristics with mammalian cells, indicating a high degree of similarity between the mammalian and Drosophila polyamine transport systems. In this report, we focused on the utility of the Drosophila epithelial model to identify and characterize polyamine transport inhibitors. We show that a previously identified inhibitor of transport in mammalian cells has a similar activity profile in Drosophila. The Drosophila model was also used to evaluate two additional transport inhibitors. We further demonstrate that a cocktail of polyamine transport inhibitors is more effective than individual inhibitors, suggesting the existence of multiple transport systems in Drosophila. Our findings reinforce the similarity between the Drosophila and mammalian transport systems and the value of the Drosophila model to provide inexpensive early screening of molecules targeting the transport system.

Highlights

The common native polyamines are a family of ubiquitous low molecular weight organic polycations containing two to four amine moieties separated by methylene groups
The effect of in mammalian cell culture is dose-dependent and typically cytostatic biosynthesis [45], intracellular polyamine levels are depleted and cell viability is decreased. The effect and this inhibition can be reversed the addition of native polyamines to the cellthis culture medium of in mammalian cell culture by is dose-dependent and typically cytostatic and inhibition can we investigated if inhibits imaginal disc development and if we the be reversed by the addition of native polyamines to the cell culture medium [14,16]
Triamide444 (9) is the most potent of the polyamine transport inhibitor (PTI) at blocking spermine uptake. These findings suggest that the PTIs have different specificities for the polyamine transport systems active in the presence of DFMO

Summary

Introduction

The common native polyamines (putrescine 1, spermidine 2 and spermine 3; Figure 1) are a family of ubiquitous low molecular weight organic polycations containing two to four amine moieties separated by methylene groups. Polyamines are essential for a variety of cellular processes including cell proliferation, transcription, translation, apoptosis and cytoskeletal dynamics [1,2,3,4]. Polyamines can bind to intracellular polyanions including nucleic acids and ATP, as well as specific proteins such as N-methyl-D-aspartate receptors and inward rectifier potassium ion channels to regulate their functions [5,6,7,8]. Difluoromethylornithine (DFMO 4; Figure 1) is an inhibitor of polyamine biosynthesis and has been.

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