A luciferase lysis assay reveals in vivo malignant cell sensitization by phosphoantigen prodrugs

Jin Li; Nicholas A Lentini; David F Wiemer; Andrew J Wiemer

doi:10.1016/j.bcp.2019.113668

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A luciferase lysis assay reveals in vivo malignant cell sensitization by phosphoantigen prodrugs

Journal article

Peer reviewed

A luciferase lysis assay reveals in vivo malignant cell sensitization by phosphoantigen prodrugs

Jin Li, Nicholas A Lentini, David F Wiemer and Andrew J Wiemer

Biochemical pharmacology, Vol.170, pp.113668-113668

12/2019

DOI: 10.1016/j.bcp.2019.113668

PMCID: PMC6910714

PMID: 31628909

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https://www.ncbi.nlm.nih.gov/pmc/articles/6910714View

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Abstract

[Display omitted] Human Vγ9Vδ2 T cells respond to small phosphorus-containing compounds, often called phosphoantigens, which are now known to be intracellular ligands of the immune receptor butyrophilin 3A1 (BTN3A1). In order to compare the efficiency of butyrophilin ligands, we developed a luciferase-based lysis assay that measures the direct cytolysis by Vγ9Vδ2 T cells of luciferase-expressing K562 leukemia cells sensitized by phosphoantigen prodrugs. Our results show that the luciferase-based lysis assay allows in vitro and in vivo assessment of phosphoantigen activity in a way that does not require the extensive processing of flow cytometry or ELISA based approaches. In cellular assays, the structure activity relationships of phosphoantigen prodrugs correlate with ELISA-based activation assays, though phosphoantigen induced target cell lysis occurs at lower concentrations relative to T cell interferon γ production measured by ELISA. In mice dosed with phosphoantigens, a racemic aryl phosphonamidate prodrug, methyl 2-[[[(E)-5-hydroxy-4-methyl-pent-3-enyl]-(1-naphthyloxy)phosphoryl]amino]acetate (1-Nap/GlyOMe C-HMBP, 5), sensitized subcutaneous K562 tumors within minutes, and this effect was maintained at least four hours after treatment. In vivo activity of compound 5 was stronger than that of an equivalent dose of zoledronate. This luciferase lysis assay can be used for evaluation of phosphoantigens due to its time efficiency, high sensitivity, and in vivo compatibility and demonstrates rapid in vitro and in vivo sensitization of tumor cells by phosphoantigen prodrugs.

Details

Title: Subtitle: A luciferase lysis assay reveals in vivo malignant cell sensitization by phosphoantigen prodrugs
Creators: Jin Li - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA
Nicholas A Lentini - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
David F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Andrew J Wiemer - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA
Resource Type: Journal article
Publication Details: Biochemical pharmacology, Vol.170, pp.113668-113668
DOI: 10.1016/j.bcp.2019.113668
PMID: 31628909
PMCID: PMC6910714
NLM abbreviation: Biochem Pharmacol
ISSN: 0006-2952
eISSN: 1873-2968
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100008893, name: University of Iowa; DOI: 10.13039/100007710, name: University of Connecticut; DOI: 10.13039/100000054, name: National Cancer Institute; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01CA186935; DOI: 10.13039/100008038, name: Herman Frasch Foundation for Chemical Research
Language: English
Date published: 12/2019
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9984216561502771

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