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

Nayoung Kim; Ji Wan Choi; Ah Young Song; Woo Seon Choi; Hye Ran Park; Sojung Park; Inki Kim; Hun Sik Kim

doi:10.1016/j.intimp.2018.12.020

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

Nayoung Kim, Ji Wan Choi, Ah Young Song, Woo Seon Choi, Hye Ran Park, Sojung Park, Inki Kim, Hun Sik Kim

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English
Pages (from-to)	152-159
Number of pages	8
Journal	International Immunopharmacology
Volume	67
DOIs	https://doi.org/10.1016/j.intimp.2018.12.020
State	Published - Feb 2019

Keywords

8-azaguanine
Cytotoxicity
Immunomodulatory drugs
Library screening
NK cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.intimp.2018.12.020

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@article{e6122e7fadf849af92475ca486ef8d3e,

title = "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.",

keywords = "8-azaguanine, Cytotoxicity, Immunomodulatory drugs, Library screening, NK cells",

author = "Nayoung Kim and Choi, {Ji Wan} and Song, {Ah Young} and Choi, {Woo Seon} and Park, {Hye Ran} and Sojung Park and Inki Kim and Kim, {Hun Sik}",

note = "Funding Information: We thank the HTS core facility of Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center. This study was supported by the Grants from the Korean Healthy Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI17C0501); MRC grant (2018R1A5A2020732) funded by the Korean government (MSIT). Funding Information: We thank the HTS core facility of Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center. This study was supported by the Grants from the Korean Healthy Technology R&D Project, Ministry of Health & Welfare, Republic of Korea ( HI17C0501 ); MRC grant ( 2018R1A5A2020732 ) funded by the Korean government ( MSIT ). Publisher Copyright: {\textcopyright} 2018 Elsevier B.V.",

year = "2019",

month = feb,

doi = "10.1016/j.intimp.2018.12.020",

language = "English",

volume = "67",

pages = "152--159",

journal = "International Immunopharmacology",

issn = "1567-5769",

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T1 - Direct potentiation of NK cell cytotoxicity by 8-azaguanine with potential antineoplastic activity

AU - Kim, Nayoung

AU - Choi, Ji Wan

AU - Song, Ah Young

AU - Choi, Woo Seon

AU - Park, Hye Ran

AU - Park, Sojung

AU - Kim, Inki

AU - Kim, Hun Sik

N1 - Funding Information: We thank the HTS core facility of Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center. This study was supported by the Grants from the Korean Healthy Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI17C0501); MRC grant (2018R1A5A2020732) funded by the Korean government (MSIT). Funding Information: We thank the HTS core facility of Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center. This study was supported by the Grants from the Korean Healthy Technology R&D Project, Ministry of Health & Welfare, Republic of Korea ( HI17C0501 ); MRC grant ( 2018R1A5A2020732 ) funded by the Korean government ( MSIT ). Publisher Copyright: © 2018 Elsevier B.V.

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

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KW - Cytotoxicity

KW - Immunomodulatory drugs

KW - Library screening

KW - NK cells

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EP - 159

JO - International Immunopharmacology

JF - International Immunopharmacology

ER -

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

Abstract

Keywords

UN SDGs

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