Medical Sciences

Editorial

3 pages, 166 KiB

Open AccessEditorial

Editorial to the Special Issue on “Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention”

by Tracy Murray Stewart

Med. Sci. 2023, 11(3), 53; https://doi.org/10.3390/medsci11030053 - 19 Aug 2023

Viewed by 1245

Abstract

To introduce this Special Issue, I refer the reader to the timely review by Zahedi and colleagues [...] Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

Research

Jump to: Editorial, Review

13 pages, 1947 KiB

Open AccessFeature PaperArticle

Polyamine Homeostasis in Snyder-Robinson Syndrome

by Tracy Murray-Stewart, Matthew Dunworth, Jackson R. Foley, Charles E. Schwartz and Robert A. Casero, Jr.

Med. Sci. 2018, 6(4), 112; https://doi.org/10.3390/medsci6040112 - 7 Dec 2018

Cited by 27 | Viewed by 5490

Abstract

Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, [...] Read more.

Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Graphical abstract

10 pages, 2470 KiB

Open AccessArticle

Polyamine Biosynthetic Pathway as a Drug Target for Osteosarcoma Therapy

by Rebecca R. Weicht, Chad R. Schultz, Dirk Geerts, Katie L. Uhl and André S. Bachmann

Med. Sci. 2018, 6(3), 65; https://doi.org/10.3390/medsci6030065 - 16 Aug 2018

Cited by 14 | Viewed by 3726

Abstract

Osteosarcoma (OS) is the most common bone tumor in children. Polyamines (PAs) are ubiquitous cations involved in many cell processes including tumor development, invasion and metastasis. In other pediatric cancer models, inhibition of the PA biosynthesis pathway with ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine [...] Read more.

Osteosarcoma (OS) is the most common bone tumor in children. Polyamines (PAs) are ubiquitous cations involved in many cell processes including tumor development, invasion and metastasis. In other pediatric cancer models, inhibition of the PA biosynthesis pathway with ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) results in decreased cell proliferation and differentiation. In OS, the PA pathway has not been evaluated. DFMO is an attractive, orally administered drug, is well tolerated, can be given for prolonged periods, and is already used in pediatric patients. Three OS cell lines were used to study the cellular effects of PA inhibition with DFMO: MG-63, U-2 OS and Saos-2. Effects on proliferation were analyzed by cell count, flow cytometry-based cell cycle analysis and RealTime-Glo™ MT Cell Viability assays. Intracellular PA levels were measured with high-performance liquid chromatography (HPLC). Western blot analysis was used to evaluate cell differentiation. DFMO exposure resulted in significantly decreased cell proliferation in all cell lines. After treatment, intracellular spermidine levels were drastically decreased. Cell cycle arrest at G₂/M was observed in U-2 OS and Saos-2. Cell differentiation was most prominent in MG-63 and U-2 OS as determined by increases in the terminal differentiation markers osteopontin and collagen 1a1. Cell proliferation continued to be suppressed for several days after removal of DFMO. Based on our findings, DFMO is a promising new adjunct to current osteosarcoma therapy in patients at high risk of relapse, such as those with poor necrosis at resection or those with metastatic or recurrent osteosarcoma. It is a well-tolerated oral drug that is currently in phase II clinical trials in pediatric neuroblastoma patients as a maintenance therapy. The same type of regimen may also improve outcomes in osteosarcoma patients in whom there have been essentially no medical advances in the last 30 years. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

12 pages, 1856 KiB

Open AccessArticle

Knocking out Ornithine Decarboxylase Antizyme 1 (OAZ1) Improves Recombinant Protein Expression in the HEK293 Cell Line

by Laura Abaandou and Joseph Shiloach

Med. Sci. 2018, 6(2), 48; https://doi.org/10.3390/medsci6020048 - 8 Jun 2018

Cited by 4 | Viewed by 4725

Abstract

Creating efficient cell lines is a priority for the biopharmaceutical industry, which produces biologicals for various uses. A recent approach to achieving this goal is the use of non-coding RNAs, microRNA (miRNA) and small interfering RNA (siRNA), to identify key genes that can [...] Read more.

Creating efficient cell lines is a priority for the biopharmaceutical industry, which produces biologicals for various uses. A recent approach to achieving this goal is the use of non-coding RNAs, microRNA (miRNA) and small interfering RNA (siRNA), to identify key genes that can potentially improve production or growth. The ornithine decarboxylase antizyme 1 (OAZ1) gene, a negative regulator of polyamine biosynthesis, was identified in a genome-wide siRNA screen as a potential engineering target, because its knock down by siRNA increased recombinant protein expression from human embryonic kidney 293 (HEK293) cells by two-fold. To investigate this further, the OAZ1 gene in HEK293 cells was knocked out using CRISPR genome editing. The OAZ1 knockout cell lines displayed up to four-fold higher expression of both stably and transiently expressed proteins, with comparable growth and metabolic activity to the parental cell line; and an approximately three-fold increase in intracellular polyamine content. The results indicate that genetic inactivation of OAZ1 in HEK293 cells is an effective strategy to improve recombinant protein expression in HEK293 cells. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

18 pages, 2184 KiB

Open AccessFeature PaperArticle

The Role of Cadaverine Synthesis on Pneumococcal Capsule and Protein Expression

by Mary F. Nakamya, Moses B. Ayoola, Seongbin Park, Leslie A. Shack, Edwin Swiatlo and Bindu Nanduri

Med. Sci. 2018, 6(1), 8; https://doi.org/10.3390/medsci6010008 - 19 Jan 2018

Cited by 14 | Viewed by 5421

Abstract

Invasive infections caused by Streptococcus pneumoniae, a commensal in the nasopharynx, pose significant risk to human health. Limited serotype coverage by the available polysaccharide-based conjugate vaccines coupled with increasing incidence of antibiotic resistance complicates therapeutic strategies. Bacterial physiology and metabolism that allows [...] Read more.

Invasive infections caused by Streptococcus pneumoniae, a commensal in the nasopharynx, pose significant risk to human health. Limited serotype coverage by the available polysaccharide-based conjugate vaccines coupled with increasing incidence of antibiotic resistance complicates therapeutic strategies. Bacterial physiology and metabolism that allows pathogens to adapt to the host are a promising avenue for the discovery of novel therapeutics. Intracellular polyamine concentrations are tightly regulated by biosynthesis, transport and degradation. We previously reported that deletion of cadA, a gene that encodes for lysine decarboxylase, an enzyme that catalyzes cadaverine synthesis results in an attenuated phenotype. Here, we report the impact of cadA deletion on pneumococcal capsule and protein expression. Our data show that genes for polyamine biosynthesis and transport are downregulated in ∆cadA. Immunoblot assays show reduced capsule in ∆cadA. Reduced capsule synthesis could be due to reduced transcription and availability of precursors for synthesis. The capsule is the predominant virulence factor in pneumococci and is critical for evading opsonophagocytosis and its loss in ∆cadA could explain the reported attenuation in vivo. Results from this study show that capsule synthesis in pneumococci is regulated by polyamine metabolism, which can be targeted for developing novel therapies. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

12 pages, 1591 KiB

Open AccessArticle

A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors

by Molly C. Peters, Allyson Minton, Otto Phanstiel IV and Susan K. Gilmour

Med. Sci. 2018, 6(1), 3; https://doi.org/10.3390/medsci6010003 - 5 Jan 2018

Cited by 18 | Viewed by 5692

Abstract

Mutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed 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. We hypothesized [...] Read more.

Mutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed 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. We hypothesized that polyamines are essential for tumor survival in mutant BRAF melanomas. These tumors rely on both polyamine biosynthesis and an upregulated polyamine transport system (PTS) to maintain their high intracellular polyamine levels. We evaluated the effect of a novel arylpolyamine (AP) compound that is cytotoxic upon cellular entry via the increased PTS activity of melanoma cells with different BRAF mutational status. Mutant BRAF melanoma cells demonstrated greater PTS activity and increased sensitivity to AP compared to wild type BRAF (BRAF^WT) melanoma cells. Treatment with an inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), further upregulated PTS activity in mutant BRAF cells and increased their sensitivity to AP. Furthermore, viability assays of 3D spheroid cultures of mutant BRAF melanoma cells demonstrated greater resistance to the BRAFi, PLX4720, compared to 2D monolayer cultures. However, co-treatment with AP restored the sensitivity of melanoma spheroids to PLX4720. These data indicate that mutant BRAF melanoma cells are more dependent on the PTS compared to BRAF^WT melanoma cells, resulting in greater sensitivity to the PTS-targeted cytotoxic AP compound. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

1145 KiB

Open AccessArticle

The ODC 3′-Untranslated Region and 5′-Untranslated Region Contain cis-Regulatory Elements: Implications for Carcinogenesis

by Shannon L. Nowotarski and Lisa M. Shantz

Med. Sci. 2018, 6(1), 2; https://doi.org/10.3390/medsci6010002 - 22 Dec 2017

Cited by 1 | Viewed by 3762

Abstract

It has been hypothesized that both the 3′-untranslated region (3′UTR) and the 5′-untranslated region (5′UTR) of the ornithine decarboxylase (ODC) mRNA influence the expression of the ODC protein. Here, we use luciferase expression constructs to examine the influence of both UTRs in keratinocyte [...] Read more.

It has been hypothesized that both the 3′-untranslated region (3′UTR) and the 5′-untranslated region (5′UTR) of the ornithine decarboxylase (ODC) mRNA influence the expression of the ODC protein. Here, we use luciferase expression constructs to examine the influence of both UTRs in keratinocyte derived cell lines. The ODC 5′UTR or 3′UTR was cloned into the pGL3 control vector upstream or downstream of the luciferase reporter gene, respectively, and luciferase activity was measured in both non-tumorigenic and tumorigenic mouse keratinocyte cell lines. Further analysis of the influence of the 3′UTR on luciferase activity was accomplished through site-directed mutagenesis and distal deletion analysis within this region. Insertion of either the 5′UTR or 3′UTR into a luciferase vector resulted in a decrease in luciferase activity when compared to the control vector. Deletion analysis of the 3′UTR revealed a region between bases 1969 and 2141 that was inhibitory, and mutating residues within that region increased luciferase activity. These data suggest that both the 5′UTR and 3′UTR of ODC contain cis-acting regulatory elements that control intracellular ODC protein levels. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

3159 KiB

Open AccessArticle

Investigation of Polyamine Metabolism and Homeostasis in Pancreatic Cancers

by Chelsea Massaro, Jenna Thomas and Otto Phanstiel IV

Med. Sci. 2017, 5(4), 32; https://doi.org/10.3390/medsci5040032 - 7 Dec 2017

Cited by 20 | Viewed by 5521

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)

► Show Figures

Graphical abstract

2347 KiB

Open AccessArticle

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

by Minpei Wang, Otto Phanstiel and Laurence Von Kalm

Med. Sci. 2017, 5(4), 27; https://doi.org/10.3390/medsci5040027 - 14 Nov 2017

Cited by 5 | Viewed by 4168

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)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

19 pages, 3872 KiB

Open AccessReview

Antizyme Inhibitors in Polyamine Metabolism and Beyond: Physiopathological Implications

by Bruno Ramos-Molina, Ana Lambertos and Rafael Peñafiel

Med. Sci. 2018, 6(4), 89; https://doi.org/10.3390/medsci6040089 - 9 Oct 2018

Cited by 14 | Viewed by 6216

Abstract

The intracellular levels of polyamines, cationic molecules involved in a myriad of cellular functions ranging from cellular growth, differentiation and apoptosis, is precisely regulated by antizymes and antizyme inhibitors via the modulation of the polyamine biosynthetic and transport systems. Antizymes, which are mainly [...] Read more.

The intracellular levels of polyamines, cationic molecules involved in a myriad of cellular functions ranging from cellular growth, differentiation and apoptosis, is precisely regulated by antizymes and antizyme inhibitors via the modulation of the polyamine biosynthetic and transport systems. Antizymes, which are mainly activated upon high polyamine levels, inhibit ornithine decarboxylase (ODC), the key enzyme of the polyamine biosynthetic route, and exert a negative control of polyamine intake. Antizyme inhibitors (AZINs), which are proteins highly homologous to ODC, selectively interact with antizymes, preventing their action on ODC and the polyamine transport system. In this review, we will update the recent advances on the structural, cellular and physiological functions of AZINs, with particular emphasis on the action of these proteins in the regulation of polyamine metabolism. In addition, we will describe emerging evidence that suggests that AZINs may also have polyamine-independent effects on cells. Finally, we will discuss how the dysregulation of AZIN activity has been implicated in certain human pathologies such as cancer, fibrosis or neurodegenerative diseases. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

16 pages, 628 KiB

Open AccessFeature PaperReview

Myc, Oncogenic Protein Translation, and the Role of Polyamines

by Andrea T. Flynn and Michael D. Hogarty

Med. Sci. 2018, 6(2), 41; https://doi.org/10.3390/medsci6020041 - 25 May 2018

Cited by 32 | Viewed by 5596

Abstract

Deregulated protein synthesis is a common feature of cancer cells, with many oncogenic signaling pathways directly augmenting protein translation to support the biomass needs of proliferating tissues. MYC’s ability to drive oncogenesis is a consequence of its essential role as a governor linking [...] Read more.

Deregulated protein synthesis is a common feature of cancer cells, with many oncogenic signaling pathways directly augmenting protein translation to support the biomass needs of proliferating tissues. MYC’s ability to drive oncogenesis is a consequence of its essential role as a governor linking cell cycle entry with the requisite increase in protein synthetic capacity, among other biomass needs. 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 regulated by MYC to increase polyamines in proliferative tissues, and this is further augmented in the many cancer cells harboring hyperactivated MYC. In this review, we discuss MYC-driven regulation of polyamines and protein synthetic capacity as a key function of its oncogenic output, and how this dependency may be perturbed through direct pharmacologic targeting of components of the protein synthetic machinery, such as the polyamines themselves, the eukaryotic translation initiation factor 4F (eIF4F) complex, and the eukaryotic translation initiation factor 5A (eIF5A). Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

13 pages, 1413 KiB

Open AccessReview

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

by T. J. Thomas and Thresia Thomas

Med. Sci. 2018, 6(1), 24; https://doi.org/10.3390/medsci6010024 - 13 Mar 2018

Cited by 13 | Viewed by 5043

Abstract

Polyamine levels are elevated in breast tumors compared to those of 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). [...] Read more.

Polyamine levels are elevated in breast tumors compared to those of 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 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 catabolizing enzyme, spermidine/spermine N¹-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

19 pages, 2152 KiB

Open AccessFeature PaperReview

Role of Polyamines in Immune Cell Functions

by Rebecca S. Hesterberg, John L. Cleveland and Pearlie K. Epling-Burnette

Med. Sci. 2018, 6(1), 22; https://doi.org/10.3390/medsci6010022 - 8 Mar 2018

Cited by 95 | Viewed by 9353

Abstract

The immune system is remarkably responsive to a myriad of invading microorganisms and provides continuous surveillance against tissue damage and developing tumor cells. To achieve these diverse functions, multiple soluble and cellular components must react in an orchestrated cascade of events to control [...] Read more.

The immune system is remarkably responsive to a myriad of invading microorganisms and provides continuous surveillance against tissue damage and developing tumor cells. To achieve these diverse functions, multiple soluble and cellular components must react in an orchestrated cascade of events to control the specificity, magnitude and persistence of the immune response. Numerous catabolic and anabolic processes are involved in this process, and prominent roles for l-arginine and l-glutamine catabolism have been described, as these amino acids serve as precursors of nitric oxide, creatine, agmatine, tricarboxylic acid cycle intermediates, nucleotides and other amino acids, as well as for ornithine, which is used to synthesize putrescine and the polyamines spermidine and spermine. Polyamines have several purported roles and high levels of polyamines are manifest in tumor cells as well in autoreactive B- and T-cells in autoimmune diseases. In the tumor microenvironment, l-arginine catabolism by both tumor cells and suppressive myeloid cells is known to dampen cytotoxic T-cell functions suggesting there might be links between polyamines and T-cell suppression. Here, we review studies suggesting roles of polyamines in normal immune cell function and highlight their connections to autoimmunity and anti-tumor immune cell function. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

15 pages, 1976 KiB

Open AccessReview

Skeletal Muscle Pathophysiology: The Emerging Role of Spermine Oxidase and Spermidine

by Manuela Cervelli, Alessia Leonetti, Guglielmo Duranti, Stefania Sabatini, Roberta Ceci and Paolo Mariottini

Med. Sci. 2018, 6(1), 14; https://doi.org/10.3390/medsci6010014 - 14 Feb 2018

Cited by 34 | Viewed by 9742

Abstract

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, [...] Read more.

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, causes muscle atrophy, a pathological state with adverse outcomes such as poor quality of life, physical disability, and high mortality. In murine skeletal muscle C2C12 cells, increased expression of the spermine oxidase (SMOX) enzyme has been found during cell differentiation. Notably, SMOX overexpression increases muscle fiber size, while SMOX reduction was enough to induce muscle atrophy in multiple murine models. Of note, the SMOX reaction product spermidine appears to be 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 D-gal-induced aging-related skeletal muscle atrophy. This review hypothesizes a role for SMOX during skeletal muscle differentiation and outlines its role and that of spermidine in muscle atrophy. The identification of new molecular pathways involved in the maintenance of skeletal muscle health could be beneficial in developing novel therapeutic lead compounds to treat muscle atrophy. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Graphical abstract

17 pages, 1317 KiB

Open AccessReview

Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases

by Nicole LoGiudice, Linh Le, Irene Abuan, Yvette Leizorek and Sigrid C. Roberts

Med. Sci. 2018, 6(1), 12; https://doi.org/10.3390/medsci6010012 - 8 Feb 2018

Cited by 49 | Viewed by 8991

Abstract

The fluorinated ornithine analog α-difluoromethylornithine (DFMO, eflornithine, ornidyl) is an irreversible suicide inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis. The ubiquitous and essential polyamines have many functions, but are primarily important for rapidly proliferating cells. Thus, ODC [...] Read more.

The fluorinated ornithine analog α-difluoromethylornithine (DFMO, eflornithine, ornidyl) is an irreversible suicide inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis. The ubiquitous and essential polyamines have many functions, but are primarily important for rapidly proliferating cells. Thus, ODC is potentially a drug target for any disease state where rapid growth is a key process leading to pathology. The compound was originally discovered as an anticancer drug, but its effectiveness was disappointing. However, DFMO was successfully developed to treat African sleeping sickness and is currently one of few clinically used drugs to combat this neglected tropical disease. The other Food and Drug Administration (FDA) approved application for DFMO is as an active ingredient in the hair removal cream Vaniqa. In recent years, renewed interest in DFMO for hyperproliferative diseases has led to increased research and promising preclinical and clinical trials. This review explores the use of DFMO for the treatment of African sleeping sickness and hirsutism, as well as its potential as a chemopreventive and chemotherapeutic agent against colorectal cancer and neuroblastoma. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Graphical abstract

12 pages, 1076 KiB

Open AccessReview

Role of Polyamines in Asthma Pathophysiology

by Vaibhav Jain

Med. Sci. 2018, 6(1), 4; https://doi.org/10.3390/medsci6010004 - 6 Jan 2018

Cited by 14 | Viewed by 8251

Abstract

Asthma is a complex disease of airways, where the interactions of immune and structural cells result in disease outcomes with airway remodeling and airway hyper-responsiveness. Polyamines, which are small-sized, natural super-cations, interact with negatively charged intracellular macromolecules, and altered levels of polyamines and [...] Read more.

Asthma is a complex disease of airways, where the interactions of immune and structural cells result in disease outcomes with airway remodeling and airway hyper-responsiveness. Polyamines, which are small-sized, natural super-cations, interact with negatively charged intracellular macromolecules, and altered levels of polyamines and their interactions have been associated with different pathological conditions including asthma. Elevated levels of polyamines have been reported in the circulation of asthmatic patients as well as in the lungs of a murine model of asthma. In various studies, polyamines were found to potentiate the pathogenic potential of inflammatory cells, such as mast cells and granulocytes (eosinophils and neutrophils), by either inducing the release of their pro-inflammatory mediators or prolonging their life span. Additionally, polyamines were crucial in the differentiation and alternative activation of macrophages, which play an important role in asthma pathology. Importantly, polyamines cause airway smooth muscle contraction and thus airway hyper-responsiveness, which is the key feature in asthma pathophysiology. High levels of polyamines in asthma and their active cellular and macromolecular interactions indicate the importance of the polyamine pathway in asthma pathogenesis; therefore, modulation of polyamine levels could be a suitable approach in acute and severe asthma management. This review summarizes the possible roles of polyamines in different pathophysiological features of asthma. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Figure 1

350 KiB

Open AccessFeature PaperReview

Regulation of Polyamine Metabolism by Curcumin for Cancer Prevention and Therapy

by Tracy Murray-Stewart and Robert A. Casero

Med. Sci. 2017, 5(4), 38; https://doi.org/10.3390/medsci5040038 - 18 Dec 2017

Cited by 24 | Viewed by 6913

Abstract

Curcumin (diferuloylmethane), the natural polyphenol responsible for the characteristic yellow pigment of the spice turmeric (Curcuma longa), is traditionally known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin [...] Read more.

Curcumin (diferuloylmethane), the natural polyphenol responsible for the characteristic yellow pigment of the spice turmeric (Curcuma longa), is traditionally known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. In human cancer cell lines, curcumin has been shown to decrease ornithine decarboxylase (ODC) activity, a rate-limiting enzyme in polyamine biosynthesis that is frequently upregulated in cancer and other rapidly proliferating tissues. Numerous studies have demonstrated that pretreatment with curcumin can abrogate carcinogen-induced ODC activity and tumor development in rodent tumorigenesis models targeting various organs. This review summarizes the results of curcumin exposure with regard to the modulation of polyamine metabolism and discusses the potential utility of this natural compound in conjunction with the exploitation of dysregulated polyamine metabolism in chemopreventive and chemotherapeutic settings. Full article

(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Polyamine Metabolism in Disease and Polyamine-Targeted Therapies

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (17 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI