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  1. Artikel ; Online: Expanded Potential of the Polyamine Analogue SBP-101 (Diethyl Dihydroxyhomospermine) as a Modulator of Polyamine Metabolism and Cancer Therapeutic

    Cassandra E. Holbert / Jackson R. Foley / Tracy Murray Stewart / Robert A. Casero

    International Journal of Molecular Sciences, Vol 23, Iss 6798, p

    2022  Band 6798

    Abstract: Naturally occurring polyamines are absolutely required for cellular growth and proliferation. Many neoplastic cells are reliant on elevated polyamine levels and maintain these levels through dysregulated polyamine metabolism. The modulation of polyamine ... ...

    Abstract Naturally occurring polyamines are absolutely required for cellular growth and proliferation. Many neoplastic cells are reliant on elevated polyamine levels and maintain these levels through dysregulated polyamine metabolism. The modulation of polyamine metabolism is thus a promising avenue for cancer therapeutics and has been attempted with numerous molecules, including enzyme inhibitors and polyamine analogues. SBP-101 (diethyl dihydroxyhomospermine) is a spermine analogue that has shown efficacy in slowing pancreatic tumor progression both in vitro and in vivo; however, the mechanisms underlying these effects remain unclear. We determined the effects of the SBP-101 treatment on a variety of cancer cell types in vitro, including lung, pancreatic, and ovarian. We evaluated the activity of enzymes involved in polyamine metabolism and the effect on intracellular polyamine pools following the SBP-101 treatment. The SBP-101 treatment produced a modest but variable increase in polyamine catabolism; however, a robust downregulation of the activity of the biosynthetic enzyme, ornithine decarboxylase (ODC), was seen across all of the cell types studied and indicates that SBP-101 likely exerts its effect predominately through the downregulation of ODC, with a minor upregulation of catabolism. Our in vitro work indicated that SBP-101 was most toxic in the tested ovarian cell lines. Therefore, we evaluated the efficacy of SBP-101 as a monotherapy in the immunosuppressive VDID8 + murine ovarian model. Mice treated with SBP-101 demonstrated a delay in tumor progression, a decrease in the overall tumor burden, and a marked increase in median survival.
    Schlagwörter polyamine ; polyamine analogue ; polyamine metabolism ; pancreatic cancer ; ovarian cancer ; cancer therapy ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2022-06-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome

    Tracy Murray Stewart / Jackson R Foley / Cassandra E Holbert / Maxim Khomutov / Noushin Rastkari / Xianzun Tao / Alex R Khomutov / R Grace Zhai / Robert A Casero Jr

    EMBO Molecular Medicine, Vol 15, Iss 11, Pp n/a-n/a (2023)

    2023  

    Abstract: Abstract Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, ... ...

    Abstract Abstract Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2‐difluoromethylornithine (DFMO), an FDA‐approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.
    Schlagwörter alpha‐methylated polyamine analogue ; eflornithine ; S‐adenosylmethionine decarboxylase ; spermidine ; spermine synthase ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2023-11-01T00:00:00Z
    Verlag Wiley
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents

    Diptesh Sil / Sudipta Panja / Chinmay M. Jogdeo / Raj Kumar / Ao Yu / Cassandra E. Holbert / Ling Ding / Jackson R. Foley / Tracy Murray Stewart / Robert A. Casero / David Oupický

    Molecules, Vol 27, Iss 2441, p

    2022  Band 2441

    Abstract: Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure–activity relationship study of the PG11047 ...

    Abstract Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure–activity relationship study of the PG11047 analogs (HPGs) containing alkyl chains of varying length, while keeping the unsaturated spermine backbone unchanged. Synthesis of higher symmetrical homologues was achieved through a synthetic route with fewer steps than the previous route to PG11047. The amphiphilic HPG analogs underwent self-assembly and formed spherically shaped nanoparticles whose size increased with the hydrophobic alkyl group’s increasing chain length. Assessment of the in vitro anticancer activity showed more than an eight-fold increase in the cancer cell inhibition activity of the analogs with longer alkyl chains compared to PG11047 in human colon cancer cell line HCT116, and a more than ten-fold increase in human lung cancer cell line A549. Evaluation of the inhibition of spermine oxidase (SMOX) showed no activity for PG11047, but activity was observed for its higher symmetrical homologues. Comparison with a reference SMOX inhibitor MDL72527 showed nine-fold better activity for the best performing HPG analog.
    Schlagwörter polyamine analogs ; PG11047 ; self-assembly ; spermine oxidase ; cancer therapy ; Organic chemistry ; QD241-441
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2022-04-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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