Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma Journal Article
| Authors: | Chen, Y. J.; Iyer, S. V.; Hsieh, D. C. C.; Li, B.; Elias, H. K.; Wang, T.; Li, J.; Ganbold, M.; Lien, M. C.; Peng, Y. C.; Xie, X. P.; Jayewickreme, C. D.; van den Brink, M. R. M.; Brady, S. F.; Lim, S. K.; Parada, L. F. |
| Article Title: | Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma |
| Abstract: | Glioblastoma is incurable and in urgent need of improved therapeutics1. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death2. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin–adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD+ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD+ pocket3. In vivo, gliocidin penetrates the blood–brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | controlled study; human tissue; protein expression; protein phosphorylation; survival rate; unclassified drug; drug activity; histopathology; area under the curve; dose response; nonhuman; temozolomide; flow cytometry; nuclear magnetic resonance imaging; brain tumor; brain neoplasms; antineoplastic agent; cell proliferation; mass spectrometry; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cell viability; gene overexpression; apoptosis; embryo; animal experiment; animal model; protein; drug screening; pathology; xenograft model antitumor assays; enzyme activity; cell line, tumor; drug synthesis; cancer inhibition; chemistry; genetic transfection; drug distribution; protein purification; glioblastoma; mammalian target of rapamycin; tumor cell line; western blotting; blood brain barrier; blood-brain barrier; plasmid; toxicity testing; gene loss; genome; hydrogen bond; models, molecular; blood cell count; kaplan meier method; tumor; drug therapy; cell transport; fluorescence activated cell sorting; fluorine nuclear magnetic resonance; phosphorus nuclear magnetic resonance; sirolimus; nad; genomic dna; autoradiography; molecular model; cell killing; fluorescence imaging; proton nuclear magnetic resonance; nicotinamide adenine dinucleotide; prodrug; carbon nuclear magnetic resonance; prodrugs; cryoelectron microscopy; nicotinamide; oligodendroglia; affinity chromatography; mammalian target of rapamycin complex 1; inosinate dehydrogenase; liquid chromatography-mass spectrometry; anion exchange chromatography; niacinamide; vulnerability; sanger sequencing; cell component; dna sequencing; humans; human; male; female; article; rna sequencing; purine synthesis; ic50; dna alkylation; crispr-cas9 system; phosphoribosyl pyrophosphate; imp dehydrogenase; inosinate dehydrogenase inhibitor; nicotinamide derivative; metabolic fingerprinting; single cell rna seq; nicotinamide-nucleotide adenylyltransferase; gliocidin; nicotinamide nucleotide adenylyltransferase |
| Journal Title: | Nature |
| Volume: | 636 |
| Issue: | 8042 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-01-01 |
| Start Page: | 466 |
| End Page: | 473 |
| Language: | English |
| DOI: | 10.1038/s41586-024-08224-z |
| PUBMED: | 39567689 |
| PROVIDER: | scopus |
| PMCID: | PMC11665509 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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