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)
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
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Interests: cancer biology; molecular basis of cancer; epigenetics; inflammation-associated carcinogenesis; polyamine metabolism
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
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polyamines in cancer
polyamines in neurodegeneration
polyamines in infection
polyamines in IRI
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: email@example.com; 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.