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Nikhil Prasad  Fact checked by:Thailand Medical News Team Dec 14, 2023  2 months, 1 week, 4 hours, 50 minutes ago

COVID-19 News: Cancer Drugs Such As HDAC1-3 Inhibitors Increases SARS-CoV-2 Replication And Infection In Lung Mesothelial And Epithelial Cells!

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COVID-19 News: Cancer Drugs Such As HDAC1-3 Inhibitors Increases SARS-CoV-2 Replication And Infection In Lung Mesothelial And Epithelial Cells!
Nikhil Prasad  Fact checked by:Thailand Medical News Team Dec 14, 2023  2 months, 1 week, 4 hours, 50 minutes ago
COVID-19 News: In the quest to understand and combat the ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), researchers from Sapienza University of Rome-Italy and the National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS-Italy, have uncovered a perplexing connection between certain cancer drugs and an increased susceptibility to SARS-CoV-2 infection in lung mesothelial and epithelial cells. This study covered in this COVID-19 News report, provides a deeper understanding of the unexpected impact of histone deacetylase (HDAC) inhibitors, specifically those targeting HDAC1-3, on the replication and infection dynamics of SARS-CoV-2.


 
Background
As the COVID-19 pandemic unfolds, the urgency to elucidate the virus's pathogenesis and identify potential therapeutic options has never been greater. Despite considerable advancements in understanding the clinical manifestations of SARS-CoV-2, gaps persist in our knowledge, and new challenges continue to emerge. This study delves into the potential role of HDAC inhibitors, a class of drugs widely used in cancer therapy, in shaping the dynamics of SARS-CoV-2 infection. The hypothesis is that these inhibitors, known for their role in modulating gene expression, might inadvertently affect the susceptibility of lung cells to SARS-CoV-2.
 
Results
The primary objective of the study was to investigate the impact of HDAC inhibition on SARS-CoV-2 infection in mesothelial cells (MCs). Utilizing MeT5A cells, a pleura MC line, the researchers subjected them to various class I and IIb HDAC inhibitors. To their astonishment, HDAC1-3 inhibitors, with a particular emphasis on MS-275, exhibited a significant increase in the expression of ACE2/TMPRSS2 – crucial receptors facilitating SARS-CoV-2 entry. This unexpected finding hinted at a potential role for HDAC inhibition in promoting SARS-CoV-2 infection.
 
The researchers validated the heightened receptor expression through various techniques, confirming the involvement of HDAC1 and HDAC2 through targeted genetic silencing. Furthermore, MS-275 demonstrated an ability to enhance SARS-CoV-2 replication and propagation in Vero E6 cells. Strikingly, this effect extended to the lung adenocarcinoma cell line Calu-3 cells, albeit to a lesser extent.
 
Mechanistically, the study unveiled that MS-275 treatment led to increased acetylation of histones H3 and H4 at ACE2/TMPRSS2 promoters, thereby enhancing their transcription. This detailed molecular insight provides a crucial link between HDAC inhibition and the increased susceptibility of cells to SARS-CoV-2 infection.
 
Discussion
The discussion segment delves into the broader context of epigenetics in the pathogenesis of SARS-CoV-2. Emphasis is placed on the intricate modulation of ACE2 and TMPRSS2 expression, which are pivotal factors governing viral entry into host cells. The study's unique contribution lies in challenging the conventional wisdom by revealing that, contrary to previous studies, most tested HDAC inhibitors increased ACE2 and TMPRSS2 expression. Among thes e inhibitors, MS-275 and MGCD0103 emerged as the most potent inducers.
 
The study explores the nuanced details of histone acetylation at ACE2 and TMPRSS2 promoters, providing a deeper understanding of how HDAC inhibition, particularly with MS-275, facilitates increased transcription. To broaden the scope, the researchers replicated their findings in a human lung epithelial cellular line, Calu-3 cells, suggesting a potential impact on cells expressing low basal levels of receptors, thereby favoring viral spreading to secondary sites of infection.
 
Furthermore, the discussion section sheds light on the broader implications of HDAC inhibitors beyond ACE2 expression. It explores how these inhibitors might modulate viral infectivity, inflammatory cytokine production, and even exhibit immunomodulatory effects. The study draws connections between these findings and ongoing clinical trials involving MS-275 in cancer therapy. However, it raises crucial concerns about the safety of these inhibitors in the context of COVID-19, particularly considering the potential for increased viral spread.
 
Conclusion
In conclusion, this in-depth analysis reveals a critical intersection between cancer drugs, specifically HDAC1-3 inhibitors, and SARS-CoV-2 infection. The unexpected role of HDAC inhibition in enhancing viral replication and infectivity through increased ACE2 and TMPRSS2 expression demands careful consideration in both basic research and translational applications. As the world grapples with the COVID-19 pandemic, these findings serve as a timely reminder of the intricate interactions between viral infections and existing therapeutic interventions. Caution is warranted in the concurrent use of HDAC inhibitors in the context of SARS-CoV-2, and further research is imperative to fully comprehend the implications of these unexpected connections.
 
The study findings were published in the peer reviewed journal: Frontiers in Cellular and Infection Microbiology.
https://www.frontiersin.org/articles/10.3389/fcimb.2023.1257683/full
 
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