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Repurposing of phosphodiesterase-5 inhibitor sildenafil as a therapeutic agent to prevent gastric cancer growth through suppressing c-MYC stability for IL-6 transcription

Zhang, Zhenzhan ; Huang, Wuqing LU orcid ; Huang, Donghua ; Xu, Zhou ; Xie, Qingfeng ; Tan, Xin ; He, Wenjun ; Yang, Weihao ; Li, Guoxin and Ji, Jianguang LU orcid , et al. (2025) In Communications Biology 8(1).
Abstract

Phosphodiesterase-5 (PDE5) inhibitors have shown promise as anti-cancer agents in malignancies. However, their specific effects on gastric cancer (GC) and the underlying mechanisms remain elusive. Our aim was to investigate this by combining evidence from population-based studies with data obtained from in vivo and in vitro experiments. By combing a couple of nationwide Swedish registers, GC patients who received PDE5 inhibitors were compared to matched controls while adjusting for confounding factors. The anti-tumor effect and mechanism of the PDE5 inhibitor sildenafil were evaluated via using tumor cells, patient-derived tumor organoids and xenograft animal models in GC. A total of 161 Swedish GC patients from a nationwide... (More)

Phosphodiesterase-5 (PDE5) inhibitors have shown promise as anti-cancer agents in malignancies. However, their specific effects on gastric cancer (GC) and the underlying mechanisms remain elusive. Our aim was to investigate this by combining evidence from population-based studies with data obtained from in vivo and in vitro experiments. By combing a couple of nationwide Swedish registers, GC patients who received PDE5 inhibitors were compared to matched controls while adjusting for confounding factors. The anti-tumor effect and mechanism of the PDE5 inhibitor sildenafil were evaluated via using tumor cells, patient-derived tumor organoids and xenograft animal models in GC. A total of 161 Swedish GC patients from a nationwide population-based cohort who received post-diagnostic PDE5 inhibitors demonstrated lower cancer-specific mortality compared to the controls (HR = 0.66, 95% CI = 0.47-0.92, P = 0.016). Functionally, the PDE5 inhibitor sildenafil exhibited the suppressive ability to prevent oncogenic growth in GC. Mechanistically, sildenafil restrained GC growth by directly activating PKG through PDE5 inhibition for regulating c-MYC expression via its phosphorylation and ubiquitination degradation, thereby suppressing c-MYC stability for IL-6 transcription within the downstream IL-6/JAK/STAT3 signalling pathway. The PDE5 inhibitor sildenafil may serve as a promising adjuvant for GC therapy if further randomized clinical trials confirm its efficacy.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Communications Biology
volume
8
issue
1
article number
85
publisher
Nature Publishing Group
external identifiers
  • scopus:85216439390
  • pmid:39827331
ISSN
2399-3642
DOI
10.1038/s42003-025-07519-9
language
English
LU publication?
no
additional info
Publisher Copyright: © The Author(s) 2025.
id
bacdcb83-98c8-469c-954e-056172aefd04
date added to LUP
2025-08-01 14:50:23
date last changed
2025-08-15 16:06:49
@article{bacdcb83-98c8-469c-954e-056172aefd04,
  abstract     = {{<p>Phosphodiesterase-5 (PDE5) inhibitors have shown promise as anti-cancer agents in malignancies. However, their specific effects on gastric cancer (GC) and the underlying mechanisms remain elusive. Our aim was to investigate this by combining evidence from population-based studies with data obtained from in vivo and in vitro experiments. By combing a couple of nationwide Swedish registers, GC patients who received PDE5 inhibitors were compared to matched controls while adjusting for confounding factors. The anti-tumor effect and mechanism of the PDE5 inhibitor sildenafil were evaluated via using tumor cells, patient-derived tumor organoids and xenograft animal models in GC. A total of 161 Swedish GC patients from a nationwide population-based cohort who received post-diagnostic PDE5 inhibitors demonstrated lower cancer-specific mortality compared to the controls (HR = 0.66, 95% CI = 0.47-0.92, P = 0.016). Functionally, the PDE5 inhibitor sildenafil exhibited the suppressive ability to prevent oncogenic growth in GC. Mechanistically, sildenafil restrained GC growth by directly activating PKG through PDE5 inhibition for regulating c-MYC expression via its phosphorylation and ubiquitination degradation, thereby suppressing c-MYC stability for IL-6 transcription within the downstream IL-6/JAK/STAT3 signalling pathway. The PDE5 inhibitor sildenafil may serve as a promising adjuvant for GC therapy if further randomized clinical trials confirm its efficacy.</p>}},
  author       = {{Zhang, Zhenzhan and Huang, Wuqing and Huang, Donghua and Xu, Zhou and Xie, Qingfeng and Tan, Xin and He, Wenjun and Yang, Weihao and Li, Guoxin and Ji, Jianguang and Liu, Hao}},
  issn         = {{2399-3642}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Communications Biology}},
  title        = {{Repurposing of phosphodiesterase-5 inhibitor sildenafil as a therapeutic agent to prevent gastric cancer growth through suppressing c-MYC stability for IL-6 transcription}},
  url          = {{http://dx.doi.org/10.1038/s42003-025-07519-9}},
  doi          = {{10.1038/s42003-025-07519-9}},
  volume       = {{8}},
  year         = {{2025}},
}