Abstract 464: Allicin, a potent new ornithine decarboxylase inhibitor in neuroblastoma

Abstract

Abstract The purpose of this study was to test if allicin inhibits ornithine decarboxylase (ODC) in pediatric neuroblastoma (NB). The natural product allicin is a reactive sulfur species (RSS) from garlic (Allium sativum L.). NB is an early childhood cancer arising from the developing peripheral nervous system. In up to 25% of cases MYCN gene amplification is correlated to high tumor stage and poor patient prognosis. High stage NB relapses frequently despite multimodal therapy and relapsed tumors are virtually untreatable. Therefore, there is a clear need for specific, novel therapeutics. MYCN transactivates the E-box gene ODC1, and the gene product ODC is a rate-limiting enzyme in polyamine biosynthesis. The increase of polyamines (putrescine, spermidine, spermine) triggers cell hyperproliferation in NB and other MYC-driven cancers through the activation of Rb-regulated cell cycle progression. ODC is a validated drug target and α-difluoromethylornithine (DFMO) is an ODC inhibitor under investigation in phase II NB trials. Although a safe drug with clinical promise, DFMO has various challenges including the need for exceptionally high treatment doses and rapid renal clearance in the urine. In an effort to identify pharmacologically superior ODC inhibitors, we identified allicin as a potent ODC inhibitor using a specific radioactive in vitro activity assay with purified ODC. Allicin also inhibited ODC activity in actively growing NB cells, reduced polyamine levels, and induced apoptosis in cell cultures. ODC is a homodimer with 12 cysteines per monomer and allicin S-thioallylates cysteines. Allicin reacts with, and is titrated-out by, low molecular weight thiols like dithiothreitol (DTT). Removal of DTT from the ODC activity assay reaction resulted in significantly higher allicin potency (IC50 at 11 nM). Although allicin has multiple cellular targets, our data reveal that one mode of action is ODC inhibition, which suppresses polyamine accumulation and induces apoptosis. The natural product allicin could be used in conjunction with other anticancer treatments, the latter at a lower than usual dosage, to achieve drug synergism with good prognosis and less side-effects. Citation Format: Chad R. Schultz, Martin C. Gruhlke, Alan J. Slusarenko, Andre S. Bachmann. Allicin, a potent new ornithine decarboxylase inhibitor in neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 464.