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Polyamines: Essential Molecules Regulating Development, Health, and Disease
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Polyamines: Essential Molecules Regulating Development, Health, and Disease

A special issue of Medical Sciences (ISSN 2076-3271). This special issue belongs to the section "Cancer and Cancer-Related Research".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 26121

Special Issue Editors

Dr. Tracy Murray-Stewart

E-Mail Website
Guest Editor
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
Interests: cancer biology; molecular basis of cancer; epigenetics; inflammation-associated carcinogenesis; polyamine metabolism
Special Issues, Collections and Topics in MDPI journals
Dr. Shannon Lyn Nowotarski

E-Mail Website
Guest Editor
Division of Science, The Pennsylvania State University Berks Campus, Reading, PA 19610, USA
Interests: cancer biology; molecular basis of cancer; epigenetics; inflammation-associated carcinogenesis; polyamine metabolism

Special Issue Information

Dear Colleagues,

Tightly controlled regulation of intracellular polyamine concentrations is necessary for normal cell growth and development. This regulation and the precise concentrations of each polyamine (putrescine, spermidine, and spermine) depend on cell type as well as microenvironmental factors. In addition to biosynthesis, the diet and microbiota are abundant sources of extracellular polyamines that can be utilized by cells. The health-promoting benefits of polyamines are a common topic of recent studies, with spermidine in particular associated with lifespan extension, autophagy, and anti-inflammatory properties. Polyamines are also critical for normal immune system activation and functioning. However, aberrant polyamine levels can lead to developmental anomalies and diseased states in various tissue and model systems. The oncogenic dysregulation of polyamine metabolism occurs across nearly all cancer types and has long been a target for cancer treatment and prevention strategies. More recently, studies investigating the impact of polyamines and polyamine-targeting therapies on the tumor microenvironment, particularly the immune component of the microenvironment, have indicated roles in determining tumor immunogenicity. Outside of cancer, several disease syndromes have now been identified that result from mutations in genes of the polyamine metabolic pathway. These syndromes provide insight into the multifaceted roles of polyamines throughout the body and their importance for normal development. This Special Issue of Medical Sciences aims to present recent advances exploring the vitality of polyamines for normal development and physiology as well as disease processes by using different model systems to address the complex roles that polyamines play in growth and development.

Dr. Tracy Murray-Stewart
Dr. Shannon Lyn Nowotarski
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • polyamines metabolism
  • putrescine
  • spermidine
  • spermine
  • polyamines in development
  • polyamines in disease
  • polyamines in health
  • polyamines in cancer
  • longevity
  • autophagy

Published Papers (9 papers)

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Research

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13 pages, 2723 KiB  
Communication
Understanding the Polyamine and mTOR Pathway Interaction in Breast Cancer Cell Growth
by Oluwaseun Akinyele and Heather M. Wallace
Med. Sci. 2022, 10(3), 51; https://doi.org/10.3390/medsci10030051 - 10 Sep 2022
Cited by 6 | Viewed by 2145
Abstract
The polyamines putrescine, spermidine and spermine are nutrient-like polycationic molecules involved in metabolic processes and signaling pathways linked to cell growth and cancer. One important pathway is the PI3K/Akt pathway where studies have shown that polyamines mediate downstream growth effects. Downstream of PI3K/Akt [...] Read more.
The polyamines putrescine, spermidine and spermine are nutrient-like polycationic molecules involved in metabolic processes and signaling pathways linked to cell growth and cancer. One important pathway is the PI3K/Akt pathway where studies have shown that polyamines mediate downstream growth effects. Downstream of PI3K/Akt is the mTOR signaling pathway, a nutrient-sensing pathway that regulate translation initiation through 4EBP1 and p70S6K phosphorylation and, along with the PI3K/Akt, is frequently dysregulated in breast cancer. In this study, we investigated the effect of intracellular polyamine modulation on mTORC1 downstream protein and general translation state in two breast cancer cell lines, MCF-7 and MDA-MB-231. The effect of mTORC1 pathway inhibition on the growth and intracellular polyamines was also measured. Results showed that polyamine modulation alters 4EBP1 and p70S6K phosphorylation and translation initiation in the breast cancer cells. mTOR siRNA gene knockdown also inhibited cell growth and decreased putrescine and spermidine content. Co-treatment of inhibitors of polyamine biosynthesis and mTORC1 pathway induced greater cytotoxicity and translation inhibition in the breast cancer cells. Taken together, these data suggest that polyamines promote cell growth in part through interaction with mTOR pathway. Similarly intracellular polyamine content appears to be linked to mTOR pathway regulation. Finally, dual inhibition of polyamine and mTOR pathways may provide therapeutic benefits in some breast cancers. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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15 pages, 4329 KiB  
Article
Identification and Characterization of Novel Small-Molecule SMOX Inhibitors
by Amelia B. Furbish, Ahmed S. Alford, Pieter Burger, Yuri K. Peterson, Tracy Murray-Stewart, Robert A. Casero, Jr. and Patrick M. Woster
Med. Sci. 2022, 10(3), 47; https://doi.org/10.3390/medsci10030047 - 30 Aug 2022
Cited by 3 | Viewed by 3422
Abstract
The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. [...] Read more.
The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, the catabolism of spermine by SMOX results in the production of toxic byproducts, including H2O2 and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded the investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of hit compounds with inhibitory activity against SMOX. We now report the discovery of potent and highly selective SMOX inhibitors 6 (IC50 0.54 μM, Ki 1.60 μM) and 7 (IC50 0.23 μM, Ki 0.46 μM), which are the most potent SMOX inhibitors reported to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of cellular injury. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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16 pages, 2159 KiB  
Article
Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy
by Cassandra E. Holbert, Jackson R. Foley, Ao Yu, Tracy Murray Stewart, Otto Phanstiel IV, David Oupicky and Robert A. Casero, Jr.
Med. Sci. 2022, 10(3), 44; https://doi.org/10.3390/medsci10030044 - 22 Aug 2022
Cited by 2 | Viewed by 1976
Abstract
Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, catabolism, and transport. Due to their continual proliferation, cancer cells maintain elevated intracellular polyamine pools. [...] Read more.
Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, catabolism, and transport. Due to their continual proliferation, cancer cells maintain elevated intracellular polyamine pools. Both polyamine metabolism and transport are commonly dysregulated in cancer, and as such, polyamine analogues are a promising strategy for exploiting the increased polyamine requirement of cancer cells. One potential polyamine analogue resistance mechanism is the downregulation of the poorly defined polyamine transport system. Recent advances in nanomedicine have produced nanostructures with polyamine analogue-based backbones (nanopolyamines). Similar nanostructures with non-polyamine backbones have been shown to be transported by endocytosis. As these polyamine-based nanoparticles could be a method for polyamine analogue delivery that bypasses polyamine transport, we designed the current studies to determine the efficacy of polyamine-based nanoparticles in cells lacking intact polyamine transport. Utilizing polyamine transport-deficient derivatives of lung adenocarcinoma lines, we demonstrated that cells unable to transport natural polyamines were also resistant to nanopolyamine-induced cytotoxicity. This resistance was a result of transport-deficient cells being incapable of importing and accumulating nanopolyamines. Pharmacological modulation of polyamine transport confirmed these results in polyamine transport competent cells. These studies provide additional insight into the polyamine transport pathway and suggest that receptor-mediated endocytosis is a likely mechanism of transport for higher-order polyamines, polyamine analogues and the nanopolyamines. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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15 pages, 1550 KiB  
Article
Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells
by Olivia El Naggar, Brenna Doyle, Kelsey Mariner and Susan K. Gilmour
Med. Sci. 2022, 10(2), 28; https://doi.org/10.3390/medsci10020028 - 26 May 2022
Cited by 4 | Viewed by 3004
Abstract
Ovarian cancer accounts for 3% of the total cancers in women, yet it is the fifth leading cause of cancer deaths among women. The BRCA1/2 germline and somatic mutations confer a deficiency of the homologous recombination (HR) repair pathway. Inhibitors of poly (ADP-ribose) [...] Read more.
Ovarian cancer accounts for 3% of the total cancers in women, yet it is the fifth leading cause of cancer deaths among women. The BRCA1/2 germline and somatic mutations confer a deficiency of the homologous recombination (HR) repair pathway. Inhibitors of poly (ADP-ribose) polymerase (PARP), another important component of DNA damage repair, are somewhat effective in BRCA1/2 mutant tumors. However, ovarian cancers often reacquire functional BRCA and develop resistance to PARP inhibitors. Polyamines have been reported to facilitate the DNA damage repair functions of PARP. Given the elevated levels of polyamines in tumors, we hypothesized that treatment with the polyamine synthesis inhibitor, α-difluoromethylornithine (DFMO), may enhance ovarian tumor sensitivity to the PARP inhibitor, rucaparib. In HR-competent ovarian cancer cell lines with varying sensitivities to rucaparib, we show that co-treatment with DFMO increases the sensitivity of ovarian cancer cells to rucaparib. Immunofluorescence assays demonstrated that, in the presence of hydrogen peroxide-induced DNA damage, DFMO strongly inhibits PARylation, increases DNA damage accumulation, and reduces cell viability in both HR-competent and deficient cell lines. In vitro viability assays show that DFMO and rucaparib cotreatment significantly enhances the cytotoxicity of the chemotherapeutic agent, cisplatin. These results suggest that DFMO may be a useful adjunct chemotherapeutic to improve the anti-tumor efficacy of PARP inhibitors in treating ovarian cancer. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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Review

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32 pages, 2588 KiB  
Review
Polyamine and Ethanolamine Metabolism in Bacteria as an Important Component of Nitrogen Assimilation for Survival and Pathogenicity
by Sergii Krysenko and Wolfgang Wohlleben
Med. Sci. 2022, 10(3), 40; https://doi.org/10.3390/medsci10030040 - 29 Jul 2022
Cited by 17 | Viewed by 4327
Abstract
Nitrogen is an essential element required for bacterial growth. It serves as a building block for the biosynthesis of macromolecules and provides precursors for secondary metabolites. Bacteria have developed the ability to use various nitrogen sources and possess two enzyme systems for nitrogen [...] Read more.
Nitrogen is an essential element required for bacterial growth. It serves as a building block for the biosynthesis of macromolecules and provides precursors for secondary metabolites. Bacteria have developed the ability to use various nitrogen sources and possess two enzyme systems for nitrogen assimilation involving glutamine synthetase/glutamate synthase and glutamate dehydrogenase. Microorganisms living in habitats with changeable availability of nutrients have developed strategies to survive under nitrogen limitation. One adaptation is the ability to acquire nitrogen from alternative sources including the polyamines putrescine, cadaverine, spermidine and spermine, as well as the monoamine ethanolamine. Bacterial polyamine and monoamine metabolism is not only important under low nitrogen availability, but it is also required to survive under high concentrations of these compounds. Such conditions can occur in diverse habitats such as soil, plant tissues and human cells. Strategies of pathogenic and non-pathogenic bacteria to survive in the presence of poly- and monoamines offer the possibility to combat pathogens by using their capability to metabolize polyamines as an antibiotic drug target. This work aims to summarize the knowledge on poly- and monoamine metabolism in bacteria and its role in nitrogen metabolism. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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18 pages, 619 KiB  
Review
Polyamines and Their Metabolism: From the Maintenance of Physiological Homeostasis to the Mediation of Disease
by Kamyar Zahedi, Sharon Barone and Manoocher Soleimani
Med. Sci. 2022, 10(3), 38; https://doi.org/10.3390/medsci10030038 - 15 Jul 2022
Cited by 10 | Viewed by 3640
Abstract
The polyamines spermidine and spermine are positively charged aliphatic molecules. They are critical in the regulation of nucleic acid and protein structures, protein synthesis, protein and nucleic acid interactions, oxidative balance, and cell proliferation. Cellular polyamine levels are tightly controlled through their import, [...] Read more.
The polyamines spermidine and spermine are positively charged aliphatic molecules. They are critical in the regulation of nucleic acid and protein structures, protein synthesis, protein and nucleic acid interactions, oxidative balance, and cell proliferation. Cellular polyamine levels are tightly controlled through their import, export, de novo synthesis, and catabolism. Enzymes and enzymatic cascades involved in polyamine metabolism have been well characterized. This knowledge has been used for the development of novel compounds for research and medical applications. Furthermore, studies have shown that disturbances in polyamine levels and their metabolic pathways, as a result of spontaneous mutations in patients, genetic engineering in mice or experimentally induced injuries in rodents, are associated with multiple maladaptive changes. The adverse effects of altered polyamine metabolism have also been demonstrated in in vitro models. These observations highlight the important role these molecules and their metabolism play in the maintenance of physiological normalcy and the mediation of injury. This review will attempt to cover the extensive and diverse knowledge of the biological role of polyamines and their metabolism in the maintenance of physiological homeostasis and the mediation of tissue injury. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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14 pages, 2736 KiB  
Review
Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses
by Alexander Chin, Charles J. Bieberich, Tracy Murray Stewart and Robert A. Casero, Jr.
Med. Sci. 2022, 10(2), 31; https://doi.org/10.3390/medsci10020031 - 10 Jun 2022
Cited by 7 | Viewed by 3327
Abstract
Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and [...] Read more.
Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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Other

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8 pages, 631 KiB  
Case Report
Two New Cases of Bachmann–Bupp Syndrome Identified through the International Center for Polyamine Disorders
by Julianne Michael, Elizabeth VanSickle, Marlie Vipond, Abby Dalman, Jeremy Prokop, Charles E. Schwartz, Surender Rajasekaran, André S. Bachmann, Magalie Barth, Clément Prouteau, Yotam Almagor, Lina Berkun, Gheona Alterescu and Caleb P. Bupp
Med. Sci. 2023, 11(2), 29; https://doi.org/10.3390/medsci11020029 - 04 Apr 2023
Cited by 1 | Viewed by 1720
Abstract
Recent identification of four additional polyaminopathies, including Bachmann–Bupp syndrome, have benefited from previous research on Snyder–Robinson syndrome in order to advance from research to treatment more quickly. As a result of the discovery of these conditions, the potential for treatment within this pathway, [...] Read more.
Recent identification of four additional polyaminopathies, including Bachmann–Bupp syndrome, have benefited from previous research on Snyder–Robinson syndrome in order to advance from research to treatment more quickly. As a result of the discovery of these conditions, the potential for treatment within this pathway, and for other possible unidentified polyaminopathies, the International Center for Polyamine Disorders (ICPD) was created to help promote understanding of these conditions, research opportunities, and appropriate care for families. This case study provides insights from two new patients diagnosed with Bachmann–Bupp syndrome, further expanding our understanding of this ultra-rare condition, as well as a general discussion about other known polyaminopathies. This work also presents considerations for collaborative research efforts across these conditions, along with others that are likely to be identified in time, and outlines the role that the ICPD hopes to fill as more patients with these polyaminopathies continue to be identified and diagnosed. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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9 pages, 1185 KiB  
Brief Report
Elucidating the Role of Chmp1 Overexpression in the Transport of Polyamines in Drosophila melanogaster
by Coryn L. Stump, Robert A. Casero, Jr., Otto Phanstiel IV, Justin R. DiAngelo and Shannon L. Nowotarski
Med. Sci. 2022, 10(3), 45; https://doi.org/10.3390/medsci10030045 - 25 Aug 2022
Cited by 2 | Viewed by 1518
Abstract
Polyamines are small organic cations that are essential for many biological processes such as cell proliferation and cell cycle progression. While the metabolism of polyamines has been well studied, the mechanisms by which polyamines are transported into and out of cells are poorly [...] Read more.
Polyamines are small organic cations that are essential for many biological processes such as cell proliferation and cell cycle progression. While the metabolism of polyamines has been well studied, the mechanisms by which polyamines are transported into and out of cells are poorly understood. Here, we describe a novel role of Chmp1, a vesicular trafficking protein, in the transport of polyamines using a well-defined leg imaginal disc assay in Drosophila melanogaster larvae. We show that Chmp1 overexpression had no effect on leg development in Drosophila, but does attenuate the negative impact on leg development of Ant44, a cytotoxic drug known to enter cells through the polyamine transport system (PTS), suggesting that the overexpression of Chmp1 downregulated the PTS. Moreover, we showed that the addition of spermine did not rescue the leg development in Chmp1-overexpressing leg discs treated with difluoromethylornithine (DFMO), an inhibitor of polyamine metabolism, while putrescine and spermidine did, suggesting that there may be unique mechanisms of import for individual polyamines. Thus, our data provide novel insight into the underlying mechanisms that are involved in polyamine transport and highlight the utility of the Drosophila imaginal disc assay as a fast and easy way to study potential players involved in the PTS. Full article
(This article belongs to the Special Issue Polyamines: Essential Molecules Regulating Development, Health, and Disease)
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