5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation
Copyright © 2024 Temizoz, Shibahara, Hioki, Hayashi, Kobiyama, Lee, Surucu, Sag, Kumanogoh, Yamamoto, Gursel, Ozen, Kuroda, Coban and Ishii..
5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative-3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xanthen-9-one (HHMX)-that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Frontiers in immunology - 15(2024) vom: 12., Seite 1353336 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Temizoz, Burcu [VerfasserIn] |
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| Links: |
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| Themen: |
0829J8133H |
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| Anmerkungen: |
Date Completed 28.03.2024 Date Revised 12.04.2024 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.3389/fimmu.2024.1353336 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370230523 |
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| 520 | |a 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative-3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xanthen-9-one (HHMX)-that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DMXAA derivative | |
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| 650 | 4 | |a SAVI | |
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| 650 | 4 | |a partial agonist | |
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| 700 | 1 | |a Shibahara, Takayuki |e verfasserin |4 aut | |
| 700 | 1 | |a Hioki, Kou |e verfasserin |4 aut | |
| 700 | 1 | |a Hayashi, Tomoya |e verfasserin |4 aut | |
| 700 | 1 | |a Kobiyama, Kouji |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Michelle Sue Jann |e verfasserin |4 aut | |
| 700 | 1 | |a Surucu, Naz |e verfasserin |4 aut | |
| 700 | 1 | |a Sag, Erdal |e verfasserin |4 aut | |
| 700 | 1 | |a Kumanogoh, Atsushi |e verfasserin |4 aut | |
| 700 | 1 | |a Yamamoto, Masahiro |e verfasserin |4 aut | |
| 700 | 1 | |a Gursel, Mayda |e verfasserin |4 aut | |
| 700 | 1 | |a Ozen, Seza |e verfasserin |4 aut | |
| 700 | 1 | |a Kuroda, Etsushi |e verfasserin |4 aut | |
| 700 | 1 | |a Coban, Cevayir |e verfasserin |4 aut | |
| 700 | 1 | |a Ishii, Ken J |e verfasserin |4 aut | |
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