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Allicin, a Potent New Ornithine Decarboxylase Inhibitor in Neuroblastoma Cells

  • Chad R. Schultz
    Chad R. Schultz
    Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, United States
    More by Chad R. Schultz
  • , 
  • Martin C. H. Gruhlke
    Martin C. H. Gruhlke
    Department of Plant Physiology, RWTH Aachen University, 52056 Aachen, Germany
    More by Martin C. H. Gruhlke
  • , 
  • Alan J. Slusarenko*
    Alan J. Slusarenko
    Department of Plant Physiology, RWTH Aachen University, 52056 Aachen, Germany
    *Tel: +49-241-80-266-50. Email: [email protected]
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  • , and 
  • André S. Bachmann*
    André S. Bachmann
    Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, United States
    *Tel: +616-234-2841. Email: [email protected]
    More by André S. Bachmann
    Orcidhttp://orcid.org/0000-0002-6510-8560
Cite this: J. Nat. Prod. 2020, 83, 8, 2518–2527
Publication Date (Web):August 12, 2020
https://doi.org/10.1021/acs.jnatprod.0c00613
Copyright © 2020 American Chemical Society and American Society of Pharmacognosy
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    Abstract

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    The natural product allicin is a reactive sulfur species (RSS) from garlic (Allium sativum L.). Neuroblastoma (NB) is an early childhood cancer arising from the developing peripheral nervous system. Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the biosynthesis of polyamines, which are oncometabolites that contribute to cell proliferation in NB and other c-MYC/MYCN-driven cancers. Both c-MYC and MYCN directly transactivate the E-box gene ODC1, a validated anticancer drug target. We identified allicin as a potent ODC inhibitor in a specific radioactive in vitro assay using purified human ODC. Allicin was ∼23 000-fold more potent (IC50 = 11 nM) than DFMO (IC50 = 252 μM), under identical in vitro assay conditions. ODC is a homodimer with 12 cysteines per monomer, and allicin reversibly S-thioallylates cysteines. In actively proliferating human NB cells allicin inhibited ODC enzyme activity, reduced cellular polyamine levels, inhibited cell proliferation (IC50 9–19 μM), and induced apoptosis. The natural product allicin is a new ODC inhibitor and could be developed for use in conjunction with other anticancer treatments, the latter perhaps at a lower than usual dosage, to achieve drug synergism with good prognosis and reduced adverse effects.

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