bims-polyam Biomed News
on Polyamines
Issue of 2025–03–02
seven papers selected by
Sebastian J. Hofer, University of Graz
  1. Putrescine Depletion in Leishmania donovani Parasites Causes Immediate Proliferation Arrest Followed by an Apoptosis-like Cell Death.
  2. Polyamines signalling pathway: A key player in unveiling the molecular mechanisms underlying Huntington's disease.
  3. Spermine attenuates TGF-β-induced EMT by downregulating fibronectin.
  4. Natural Polyamine Spermidine Inhibits the In Vitro Oxidation of LDL.
  5. Polyamine depletion limits progression of acute leukaemia.
  6. Polyamine Inhibition with DFMO: Shifting the Paradigm in Neuroblastoma Therapy.
  7. Targeting SMOX Preserves Optic Nerve Myelin, Axonal Integrity, and Visual Function in Multiple Sclerosis.
  1. Pathogens. 2025 Feb 02. pii: 137. [Epub ahead of print]14(2):
    Putrescine Depletion in Leishmania donovani Parasites Causes Immediate Proliferation Arrest Followed by an Apoptosis-like Cell Death.
    Julia Johnston, Jonathan Taylor, Surbhi Nahata, Angelica Gatica-Gomez, Yvette L Anderson, Sophia Kiger, Thong Pham, Kayhan Karimi, Jasmin-Faith Lacar, Nicola S Carter, Sigrid C Roberts.
      The polyamine pathway in Leishmania parasites has emerged as a promising target for therapeutic intervention, yet the functions of polyamines in parasites remain largely unexplored. Ornithine decarboxylase (ODC) and spermidine synthase (SPDSYN) catalyze the sequential conversion of ornithine to putrescine and spermidine. We previously found that Leishmania donovani Δodc and Δspdsyn mutants exhibit markedly reduced growth in vitro and diminished infectivity in mice, with the effect being most pronounced in putrescine-depleted Δodc mutants. Here, we report that, in polyamine-free media, ∆odc mutants arrested proliferation and replication, while ∆spdsyn mutants showed a slow growth and replication phenotype. Starved ∆odc parasites also exhibited a marked reduction in metabolism, which was not observed in the starved ∆spdsyn cells. In contrast, both mutants displayed mitochondrial membrane hyperpolarization. Hallmarks of apoptosis, specifically DNA fragmentation and membrane modifications, were observed in Δodc mutants incubated in polyamine-free media. These results show that putrescine depletion had an immediate detrimental effect on cell growth, replication, and mitochondrial metabolism and caused an apoptosis-like death phenotype. Our findings establish ODC as the most promising therapeutic target within the polyamine biosynthetic pathway for treating leishmaniasis.
    Keywords:  Leishmania; apoptosis; mitochondria; ornithine decarboxylase; polyamines; replication; spermidine synthase; starvation
    DOI:  https://doi.org/10.3390/pathogens14020137
  2. Neuroscience. 2025 Feb 20. pii: S0306-4522(25)00160-5. [Epub ahead of print]570 213-224
    Polyamines signalling pathway: A key player in unveiling the molecular mechanisms underlying Huntington's disease.
    Amit Shiwal, Dhanshree Nibrad, Manasi Tadas, Raj Katariya, Mayur Kale, Nitu Wankhede, Nandkishor Kotagale, Milind Umekar, Brijesh Taksande.
      Polyaminesare essential organic cations found in all eukaryotic cells and play an important role in many cellular processes including growth, differentiation, andneuroprotection. This review explores the complex relationship between polyamine signaling and Huntington's disease (HD), an autosomal-dominant neurodegenerative disorder characterized by the progressive degeneration of medium-spiny neurons in the striatum and cortex due to mutations in the huntingtin gene. We provide a comprehensive overview of how polyamines, specificallyputrescine,spermidine, andspermine, regulate important cellular functions such as gene expression, protein synthesis, membrane stability, and ion channel regulation with implications for HD. Dysfunction in polyamine metabolism in HD, reveals how changes in these molecules promote oxidative stress, mitochondrial dysfunction, andexcitotoxicity. Importantly, polyamines interact with mutanthuntingtin protein (mHTT) to affect its aggregationand neurotoxicity. This effect may contribute to the pathophysiological mechanisms underlying HD, suggesting that polyamines may act as potential biomarkers of disease progression. Additionally, we discuss the therapeutic implications of targeting the polyamine signaling pathway to alleviate HD symptoms. By enhancing autophagy and modulating neurotransmitter systems, polyamines mayprovideneuroprotectionagainstmHTT-inducedtoxicity. Moreover, the present review provides new insight into the role of polyamines in the pathogenesis of HDand suggests that regulation of polyamine metabolism may represent a promising therapy to slow the disease progression. Besides this, the review highlights the need for further investigation of the diverse roles of polyamines in neurodegenerative diseases, including HD, paving the way for novel interventions to improve cellular homeostasis andpatient outcomes.
    Keywords:  Huntington’s disease; Polyamine signaling; Putrescine; Spermidine; Spermine
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.02.042
  3. J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00201-7. [Epub ahead of print] 108352
    Spermine attenuates TGF-β-induced EMT by downregulating fibronectin.
    Huidong Liu, Ye-Guang Chen.
      Epithelial-mesenchymal transition (EMT) is a highly dynamic cellular process that occurs in development, tissue repair and cancer metastasis. As a master EMT inducer, TGF-β can activate the EMT program by regulating the expression of key EMT-related genes and triggering other required cellular changes. However, it is unclear whether cell metabolism is involved in TGF-β-induced EMT. Here, we characterized early metabolic changes in response to transient TGF-β stimulation in HaCaT cells and discovered that TGF-β signaling significantly reduces the intracellular polyamine pool. Exogenous addition of spermine, but not other polyamines, attenuates TGF-β-induced EMT. Mechanistically, spermine downregulates the extracellular matrix protein fibronectin. Furthermore, we found that TGF-β activates ERK to enhance the expression of spermine oxidase, which is responsible for the reduced spermine concentration. This action of TGF-β on EMT via the polyamine metabolism provides new insights into the mechanisms underlying EMT and might be exploited as a way to target the EMT program for therapy.
    Keywords:  EMT; TGF-β; fibronectin; polyamine metabolism; spermine
    DOI:  https://doi.org/10.1016/j.jbc.2025.108352
  4. Molecules. 2025 Feb 19. pii: 955. [Epub ahead of print]30(4):
    Natural Polyamine Spermidine Inhibits the In Vitro Oxidation of LDL.
    Christine Rossmann, Azra Darko, Gerd Kager, Gerhard Ledinski, Willibald Wonisch, Thomas Wagner, Seth Hallström, Gilbert Reibnegger, Margret Paar, Gerhard Cvirn.
      Spermidine is a natural autophagy-inducer and anti-aging compound. Herein, we investigated a potential autophagy-independent mechanism of spermidine, namely its capability to directly impede LDL oxidation, an early step in atherogenesis. In our in vitro-model, LDL oxidation was induced by the addition of CuCl2 in the presence of increasing concentrations of spermidine, and the degree of oxidation of the lipid, as well as of the protein part of LDL, was measured. We found that spermidine concentration-dependently inhibited the production of lipid hydroperoxides, malondialdehyde, and oxidation-specific immune epitopes in the LDL particle, associated with decreased relative electrophoretic mobilities, respectively. For example, the LPO content was significantly lower when LDL was oxidized in the presence of 500 µg/mL spermidine (26.9 ± 1.6 nmol/mg LDL) than in the absence of spermidine (180.6 ± 7.7 nmol/mg LDL, p < 0.0001). When oxLDL was obtained under increasing spermidine concentrations, its cytotoxicity in EA.hy926 cells concentration-dependently decreased. Quantum chemical calculations show that the reaction between spermidine and hydroxyl radicals is exergonic. We conclude that spermidine is a direct inhibitor of LDL oxidation due to its capability to scavenge hydroxyl radicals. Thus, spermidine supplementation might be a suitable tool to impede atherogenesis and associated (cardio)vascular diseases. Further prospective clinical studies are needed to evaluate the potential atheroprotective/health-promoting effects of spermidine-rich diets.
    Keywords:  antioxidants; atherogenesis; copper ions; endothelial damage; lipid oxidation
    DOI:  https://doi.org/10.3390/molecules30040955
  5. Int J Cancer. 2025 Feb 22.
    Polyamine depletion limits progression of acute leukaemia.
    Weiman Gao, Mawar Karsa, Lin Xiao, Dayna Spurling, Ayu Karsa, Emma Ronca, Angelika Bongers, Xinyi Guo, Chelsea Mayoh, Mujahid Azfar, Steven H L Verhelst, Katsunori Tanaka, Laurence C Cheung, Rishi S Kotecha, Richard B Lock, Mark R Burns, Peter Vangheluwe, Murray D Norris, Michelle Haber, Klaartje Somers.
      Cancer cells are addicted to polyamines, polycations essential for cellular function. While dual targeting of cellular polyamine biosynthesis and polyamine uptake is under clinical investigation in solid cancers, preclinical and clinical studies into its potential in haematological malignancies are lacking. Here we investigated the preclinical efficacy of polyamine depletion in acute leukaemia. The polyamine biosynthesis inhibitor difluoromethylornithine (DFMO) inhibited growth of a molecularly diverse panel of acute leukaemia cell lines, while non-malignant cells were unaffected. Responsiveness to DFMO was linked to decreased levels of its molecular target, the rate-limiting polyamine biosynthesis enzyme ODC1, and of the polyamine transporters ATP13A2 and ATP13A3. DFMO increased polyamine uptake and upregulated expression of polyamine transporters in acute leukaemia cells, a compensatory effect abolished by treatment with the polyamine transport inhibitor AMXT 1501. This drug, currently in a phase 1 clinical trial in solid tumours in combination with DFMO, potentiated the inhibitory effects of DFMO, and their combination synergistically inhibited the growth of acute leukaemia cell lines by inducing apoptosis. DFMO and AMXT 1501 limited disease progression in highly aggressive xenograft models of infant KMT2A-rearranged leukaemia, even when treatment was initiated at high disease burden. Increased expression of c-MYC was associated with enhanced sensitivity to the combination of DFMO and AMXT 1501, suggesting this oncoprotein as a potential predictive marker of response to the drug combination. In conclusion, targeting polyamine biosynthesis and polyamine uptake limits disease progression in models of acute leukaemia, supporting further preclinical and clinical investigation into this approach for acute leukaemia.
    Keywords:  DFMO; acute leukaemia; polyamine depletion; polyamine transport; polyamines
    DOI:  https://doi.org/10.1002/ijc.35362
  6. J Clin Med. 2025 Feb 07. pii: 1068. [Epub ahead of print]14(4):
    Polyamine Inhibition with DFMO: Shifting the Paradigm in Neuroblastoma Therapy.
    Joseph Schramm, Chloe Sholler, Leah Menachery, Laura Vazquez, Giselle Saulnier Sholler.
      Neuroblastoma is a common childhood malignancy, and high-risk presentations, including an MYCN amplified status, continue to result in poor survival. Difluoromethylornithine (DFMO) is a new and well-tolerated treatment for high-risk neuroblastoma. This review article discusses preclinical and clinical data that resulted in the establishment of DFMO as a treatment for neuroblastoma. The review of preclinical data includes a summary of the contribution of polyamine synthetic pathways to high-risk neuroblastoma, the effect that MYCN has on polyamine synthetic pathways, and the proposed mechanism by which DFMO inhibits tumorigenesis. This understanding has led to the discussion of various preclinical combination therapies that may result in a synergistic therapeutic response for high-risk neuroblastoma. We review the clinical trials that show the successful treatment of high-risk neuroblastoma with DFMO, including comparative analysis and traditional neuroblastoma trials using propensity score matching. We review the regulatory path by which DFMO gained approval from the Federal Drug Administration for use as a maintenance therapy following the traditional high-risk neuroblastoma therapy. Finally, we discuss the role of DFMO in future clinical research for neuroblastoma and additional pediatric cancers.
    Keywords:  DFMO; LIN28; neuroblastoma; review
    DOI:  https://doi.org/10.3390/jcm14041068
  7. Biomolecules. 2025 Jan 21. pii: 158. [Epub ahead of print]15(2):
    Targeting SMOX Preserves Optic Nerve Myelin, Axonal Integrity, and Visual Function in Multiple Sclerosis.
    Harry O Henry-Ojo, Fang Liu, S Priya Narayanan.
      Multiple sclerosis (MS) is a highly disabling chronic neurological condition affecting young adults. Inflammation, demyelination, and axonal damage are key pathological features of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Our previous work demonstrated that inhibiting spermine oxidase (SMOX) with MDL72527, a selective irreversible pharmacological inhibitor, significantly reduced clinical symptoms, retinal ganglion cell (RGC) loss, and optic nerve inflammation in EAE mice. The present study explored the broader therapeutic potential of SMOX inhibition, focusing on myelin preservation, axonal integrity, and visual function in the EAE model. Electron microscopy of optic nerve cross-sections showed significant preservation of myelin thickness and axonal integrity due to SMOX inhibition. The quantitative assessment showed that g-ratio and axon count metrics were significantly improved in MDL72527-treated EAE mice compared to their vehicle-treated counterparts. Immunofluorescence studies confirmed these findings, showing increased preservation of myelin and axonal proteins in MDL72527-treated EAE mice compared to the vehicle-treated group. Functional assessment studies (Electroretinography) demonstrated significant improvement in RGC function and axonal conduction in EAE mice treated with MDL72527. Furthermore, SMOX inhibition downregulated the expression of galectin3 (Gal3), a mediator of neuroinflammation, indicating Gal3's role in SMOX-mediated neuroprotection. This study provides compelling evidence for the potential of SMOX inhibition as a therapeutic strategy in multiple sclerosis and other demyelinating disorders.
    Keywords:  MDL72527; multiple sclerosis; myelin; optic nerve; spermine oxidase; vision
    DOI:  https://doi.org/10.3390/biom15020158
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒15 at 20:16.