Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response

Imai, Hideki; Dansako, Hiromichi; Ueda, Youki; Satoh, Shinya; Kato, Naoya

doi:10.1016/j.bbrc.2018.08.195

Cited by 20 publications

(19 citation statements)

References 34 publications

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“…Overall, the report suggests that doxorubicin-mediated IFN activation may be due to two distinct, ATM- or STING-dependent pathways. Another recent paper on hepatitis B virus (HBV) showed that daunorubicin can trigger innate immune response in a cGAS-dependent manner preventing HBV production in human hepatocytes [ 131 ]. Therefore, overall these results support the fact that anthracyclines can activate the STING-cGAS pathway activating type I interferons in cancer cells.…”

Section: Interactions Of Anthracyclines With the Immune Systemmentioning

confidence: 99%

Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives

Marinello

Delcuratolo

Capranico

2018

IJMS

182

140

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Mammalian DNA topoisomerases II are targets of anticancer anthracyclines that act by stabilizing enzyme-DNA complexes wherein DNA strands are cut and covalently linked to the protein. This molecular mechanism is the molecular basis of anthracycline anticancer activity as well as the toxic effects such as cardiomyopathy and induction of secondary cancers. Even though anthracyclines have been used in the clinic for more than 50 years for solid and blood cancers, the search of breakthrough analogs has substantially failed. The recent developments of personalized medicine, availability of individual genomic information, and immune therapy are expected to change significantly human cancer therapy. Here, we discuss the knowledge of anthracyclines as Topoisomerase II poisons, their molecular and cellular effects and toxicity along with current efforts to improve the therapeutic index. Then, we discuss the contribution of the immune system in the anticancer activity of anthracyclines, and the need to increase our knowledge of molecular mechanisms connecting the drug targets to the immune stimulatory pathways in cancer cells. We propose that the complete definition of the molecular interaction of anthracyclines with the immune system may open up more effective and safer ways to treat patients with these drugs.

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Section: Interactions Of Anthracyclines With the Immune Systemmentioning

confidence: 99%

Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives

Marinello

Delcuratolo

Capranico

2018

IJMS

182

140

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“…Thus, further investigation of their roles in HBV infection is warranted. Although activation of the cGAS-STING pathway was demonstrated to be able to inhibit HBV replication in cell culture and mice (7,15,18,40), HBV could also actively suppress cGAS expression and function in vitro and humanized liver chimeric mice (40). Our results showed cGAS expression level was not altered in chronic HBV patients, suggesting HBV may evade from cGAS sensing.…”

Section: Discussionmentioning

confidence: 63%

Hepatitis B Virus Might Be Sensed by STING-Dependent DNA Sensors and Attenuates the Response of STING-Dependent DNA Sensing Pathway in Humans with Acute and Chronic Hepatitis B Virus Infection

Chen

et al. 2020

Viral Immunology

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DNA-dependent activator of interferon regulatory factors (DAIs), interferon gamma inducible protein 16 (IFI16), DEAD-box polypeptide 41 (DDX41), DNA-dependent protein kinase (DNA-PK), meiotic recombination 11 homolog A (MRE11), and cyclic GMP-AMP synthase (cGAS) have been identified as intracellular STING-dependent DNA sensors in recent years. Studies have shown that the DNA sensor-STING-interferon (IFN)-b pathway plays an important role in the defense against intracellular invasion of many DNA viruses. However, the intracellular recognition of hepatitis B virus (HBV) DNA by DNA sensors is still largely unclear. In this study, we aimed to determine whether the DNA sensor-STING pathway in peripheral blood mononuclear cells (PBMCs) can be activated by acute and chronic HBV infections in humans. We first evaluated the expression of these DNA sensors in PBMCs of acute and chronic HBV-infected patients by quantitative realtime polymerase chain reaction. We next compared the expression of the upregulated DNA sensor between monocytes and nonmonocytes to find its cellular source. Finally, by in vitro stimulation, we analyzed the IFN-b response of the DNA sensor-STING pathway in PBMCs and monocytes from chronic HBV-infected patients. The results showed that IFI16, DDX41, MRE11, and the adaptor STING were upregulated in chronic HBVinfected patients, whereas only IFI16 was upregulated in acute HBV-infected patients. However, IFN-b expression was not changed in PBMCs from acute and chronic HBV-infected patients. We next found IFI16 was mainly expressed in monocytes of acute and chronic hepatitis B patients. Finally, by stimulation of monocytes with VACV ds 70mer, a ligand for IFI16, we confirmed the attenuated response of the IFI16-STING pathway. Taken together, our results suggest that HBV might be sensed by DNA sensors in PBMCs of acute and chronic HBV-infected patients, and meanwhile HBV infection attenuates the response of the DNA sensor-STING pathway in PBMCs and monocytes, which may facilitate the persistence of HBV infection.

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“…Thus, further investigation of their roles in HBV infection is warranted. Although activation of the cGAS-STING pathway was demonstrated to be able to inhibit HBV replication in cell culture and mice[18][19][45][46], HBV could also actively suppress cGAS expression and function in vitro and humanized liver chimeric mice[46]. Our results showed cGAS expression level was not altered in chronic HBV patients, suggesting HBV may evade from cGAS sensing.…”

mentioning

confidence: 63%

Hepatitis B Virus Can Be Sensed by STING-dependent DNA Sensors but Suppresses the DNA Sensing Pathway in Humans with Acute and Chronic Hepatitis B Virus Infection

Chen¹,

He²,

Chen³

et al. 2020

Preprint

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Background : With the discovery of stimulator of interferon genes (STING) in 2008, many intracellular molecules have been identified as STING-dependent DNA sensors in recent years. Studies show the DNA sensor-STING-IFN-β pathway plays an important role in defense against viral infections. However, the recognition of hepatitis B virus (HBV) by DNA sensors is still largely unclear. In this study, we aimed to investigate the role of STING-dependent DNA sensors in HBV infection. Methods: The expression of these DNA sensors in PBMCs from patients with acute and chronic HBV infection was analyzed by quantitative real-time PCR. The cellular source of the upregulated DNA sensor and the response of the corresponding sensing pathway in PBMCs from HBV-infected patients were also investigated. Results: The expression of interferon gamma inducible protein 16 (IFI16), DEAD-box polypeptide 41 (DDX41), meiotic recombination 11 homolog A (MRE11), and STING were upregulated in chronic HBV-infected patients, whereas only IFI16 expression increased in acute HBV-infected patients. However, no IFN-β induction was observed in PBMCs in either acute or chronic HBV-infected patients. We next found IFI16 was mainly expressed in monocytes from acute and chronic hepatitis B patients. By stimulation of monocytes with VACV ds 70mer, an agonist ligand for IFI16, we confirmed the suppressed response of the IFI16-STING pathway in chronic HBV infection. Conclusions: Our results suggest that HBV can be sensed by DNA sensors in PBMCs in both acute and chronic HBV-infected patients and meanwhile actively counteract the DNA sensing pathway in PBMCs, which may facilitate the persistence of HBV infection.

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Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response

Cited by 20 publications

References 34 publications

Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives

Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives

Hepatitis B Virus Might Be Sensed by STING-Dependent DNA Sensors and Attenuates the Response of STING-Dependent DNA Sensing Pathway in Humans with Acute and Chronic Hepatitis B Virus Infection

Hepatitis B Virus Can Be Sensed by STING-dependent DNA Sensors but Suppresses the DNA Sensing Pathway in Humans with Acute and Chronic Hepatitis B Virus Infection

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