Direct potentiation of NK cell cytotoxicity by 8-azaguanine with potential antineoplastic activity.

Abstract

This study identified 8-azaguanine (8-AG) as a novel immunomodulatory drug (IMiD) through a high-throughput screen of the Preswick Chemical Library in a model of human NK cell cytotoxicity against blood cancer cells. 8-AG, originally developed as an antineoplastic agent, significantly increased the cytotoxicity of NK cells and was superior in this activity to previously known IMiDs, such as fluoxetine and amphotericin B, identified from the same library. IFN-γ expression was also slightly increased by 8-AG. Mechanistically, 8-AG increased conjugate formation between NK and target cells and subsequent cytolytic granule polarization, but not calcium mobilization, regulation of activating receptors, or expression of perforin or granzyme B. Thus, the antineoplastic activity of 8-AG should be re-evaluated in light of this novel potentiating effect on NK cells.

• Authors: Nayoung Kim, Ji-Wan Choi, Ah Young Song, Woo Seon Choi, Hye-Ran Park, Sojung Park, Inki Kim, Hun Sik Kim
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 67 Pg. 152-159 (Feb 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 30551032 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Immunologic Factors
• Small Molecule Libraries
• Fluoxetine
• Perforin
• Amphotericin B
• Granzymes
• Azaguanine

Topics

• Amphotericin B (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Azaguanine (therapeutic use)
• Cells, Cultured
• Cytoplasmic Granules (metabolism)
• Cytotoxicity, Immunologic
• Drug Screening Assays, Antitumor
• Fluoxetine (therapeutic use)
• Granzymes (metabolism)
• Hematologic Neoplasms (drug therapy)
• Humans
• Immunologic Factors (therapeutic use)
• Killer Cells, Natural (immunology)
• Lymphocyte Activation
• Perforin (genetics, metabolism)
• Small Molecule Libraries