Special Issue "Polyamine Metabolism in Disease and Polyamine-Targeted Therapies"

A special issue of Medical Sciences (ISSN 2076-3271).

Deadline for manuscript submissions: closed (30 November 2017)

Special Issue Editor

Guest Editor
Dr. Tracy Murray-Stewart

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Department of Cancer Biology, 1650 Orleans Street, Baltimore, MD 21287
Website | E-Mail
Interests: cancer biology; molecular basis of cancer; epigenetics; inflammation-associated carcinogenesis; polyamine metabolism

Special Issue Information

Dear Colleagues,

Polyamines are ubiquitous polycations essential for all cellular life. The most common polyamines in eukaryotes, spermine, spermidine, and putrescine, exist in millimolar intracellular concentrations that are tightly regulated through biosynthesis, catabolism, and transport. Polyamines interact with, and regulate, negatively charged macromolecules, including nucleic acids, proteins, and ion channels. Accordingly, alterations in polyamine metabolism affect cellular proliferation and survival through changes in gene expression and transcription, translation, autophagy, oxidative stress, and apoptosis. Dysregulation of these multifaceted polyamine functions contribute to multiple disease processes, thus their metabolism and function have been targeted for preventive or therapeutic intervention. The correlation between elevated polyamine levels and cancer is well established, and ornithine decarboxylase, the rate-limiting biosynthetic enzyme in the production of putrescine, is a bona fide transcriptional target of the Myc oncogene. Furthermore, induced polyamine catabolism contributes to carcinogenesis that is associated with certain forms of chronic infection and/or inflammation through the production of reactive oxygen species. These and other characteristics specific to cancer cells have led to the development of polyamine-based agents and inhibitors aimed at exploiting the polyamine metabolic pathway for chemotherapeutic and chemopreventive benefit. In addition to cancer, polyamines are involved in the pathologies of neurodegenerative diseases including Alzheimer’s and Parkinson’s, parasitic and infectious diseases, wound healing, ischemia/reperfusion injuries, and certain age-related conditions, as polyamines are known to decrease with age. As in cancer, polyamine-based therapies for these conditions are an area of active investigation. With recent advances in immunotherapy, interest has increased regarding polyamine-associated modulation of immune responses, as well as potential immunoregulation of polyamine metabolism, the results of which could have relevance to multiple disease processes. The goal of this Special Issue of Medical Sciences is to present the most recent advances in polyamine research as it relates to health, disease, and/or therapy.

Dr. Tracy Murray-Stewart
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Medical Sciences is an international peer-reviewed open access quarterly journal published by MDPI.

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Keywords

  • polyamine analogue

  • ornithine decarboxylase

  • spermine, spermidine

  • putrescine

  • polyamines in cancer

  • polyamines in neurodegeneration

  • polyamines in infection

  • polyamines in IRI

Published Papers (2 papers)

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Research

Open AccessArticle Investigation of Polyamine Metabolism and Homeostasis in Pancreatic Cancers
Med. Sci. 2017, 5(4), 32; doi:10.3390/medsci5040032
Received: 7 November 2017 / Revised: 4 December 2017 / Accepted: 5 December 2017 / Published: 7 December 2017
PDF Full-text (3159 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)
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Open AccessArticle Evaluation of Polyamine Transport Inhibitors in a Drosophila Epithelial Model Suggests the Existence of Multiple Transport Systems
Med. Sci. 2017, 5(4), 27; doi:10.3390/medsci5040027
Received: 17 October 2017 / Revised: 8 November 2017 / Accepted: 9 November 2017 / Published: 14 November 2017
PDF Full-text (2347 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

T.J. Thomas and Thresia Thomas

Departments of Medicine and Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA

Abstract: Polyamine levels are elevated in breast tumors compared to that in adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was some degree of structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catobilizing enzyme, spermidine/spermine N-1 acetyl transferase (SSAT) was increased by up to 6-fold by bis(ethyl)norspermine. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. The reduction in polyamine levels and ODC activity was similar to that found with cell line models. This paper will review our research in this area, with a comparative evaluation of reports from other laboratories.

 

Pathophysiological role of spermine oxidase in skeletal muscle

Cervelli M., Leonetti A., Duranti G., Ceci R., Mariottini P.

Background: Skeletal muscle atrophy is a common state that lacks an effective therapy. Loss of strength from muscle atrophy limits activity, impairs life quality and leads to falls and fractures. Aging worsens this scenario and brings to a condition often referred to as sarcopenia. Methods: Review. Results: It has been shown that in diverse models of muscle atrophy, polyamines metabolism is altered. Notably, spermine oxidase (SMOX) decrease is sufficient to induce muscle atrophy; whereas, a forced expression of SMOX increases muscle fiber size in multiple models of muscle atrophy. Furthermore, in murine skeletal muscle C2C12 cells, an increased expression of the SMOX enzyme was observed during cells differentiation. The SMOX reaction product spermidine appears to be the primary polyamine involved in skeletal muscle atrophy/hypertrophy. It is effective in reactivating autophagy, ameliorating the myopathic defects of collagen VI-null mice. Moreover, spermidine treatment, if combined with exercise, can affect the D-gal-induced aging-related skeletal muscle atrophy. Conclusion: This review outlines the role of polyamine metabolism, in particular of SMOX, in muscle atrophy. The recently identified new molecular pathways involved in atrophy need to be further investigated for developing novel therapeutic lead compounds to treat muscle atrophy.

 

A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors

Molly Peters1, Allyson Minton1, Eric Alexander1, Otto Phanstiel2, and Susan Gilmour1

1Lankenau Institute for Medical Research, Wynnewood, PA  

2 University of Central Florida, Orlando, FL

Abstract: BRAF mutations are present in over half of all melanoma tumors.  Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time and are resistant to further treatment with these drugs.  We hypothesized that polyamines are essential for tumor survival in mutant BRAF melanomas, and that these tumors require high levels of polyamines and possess an upregulated polyamine transport system (PTS).  We evaluated the effect of a novel arylpolyamine (AP) drug that is cytotoxic upon cellular internalization via the increased PTS activity in melanoma cells with different BRAF mutational status.  BRAFV600E melanoma cells demonstrated greater PTS activity and increased sensitivity to AP (lower IC50) compared to BRAFWT melanoma cells.  Treatment with an inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), upregulated PTS activity in BRAFV600E melanoma cells and further increased their sensitivity to AP.   Furthermore, a human BRAFV600E melanoma WM983B-BR subline with acquired BRAF inhibitor resistance demonstrated increased PTS activity compared to parental BRAF inhibitor-sensitive WM983B cells.  These data indicate that utilizing the PTS for drug delivery with a novel polyamine cytotoxic drug attacks mutant BRAF melanoma tumor cells via one of their key modes of survival. 

 

Myc-driven oncogenesis, protein translation, and the role of polyamines

Andrea T. Flynn 1,2 and Michael D. Hogarty 1,2

1   Children’s Hospital of Philadelphia, Philadelphia, PA 19104

2   University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104

*   Correspondence: flynna@email.chop.edu; Tel.: +01-267-425-1920

Deregulated protein translation is a common feature of cancer cells, as many oncogenic signaling pathways lead directly to increased protein synthesis to support the biomass needs of proliferative tissues. MYC’s ability to drive oncogenesis is a consequence of its role as a governor linking cell cycle entry with the requisite increase in protein synthetic capacity (among other biomass needs) and energetics. To date, direct pharmacologic inhibition of Myc has proven difficult, but targeting oncogenic signaling modules downstream of Myc, such as the protein synthetic machinery, may provide a viable therapeutic strategy. Polyamines are essential cations found in nearly all living organisms that have both direct and indirect roles in the control of protein synthesis. Polyamine metabolism is coordinately deregulated by activated MYC, with high levels of polyamines present in most cancer tissues. In this review, we discuss Myc-driven regulation of protein synthetic capacity as a key function of oncogenesis, and how this dependency may be perturbed through direct pharmacologic targeting of components of the protein synthetic machinery such as eIF5A and the eIF4F complex. 

 

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