ArticleCancer prevention research (Philadelphia, Pa.)2011
Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells.
Article in Cancer prevention research (Philadelphia, Pa.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 112 citations in OpenAlex.
- Aging modulation of the immune system and immunotherapy efficacy in cancer.Frontiers in immunology · 2026Review
- NSAID-encapsulated nanoparticles as a targeted therapeutic platform for modulating chronic inflammation and inhibiting cancer progression: a review.Inflammopharmacology · 2025Review
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- PDE10A as a novel diagnostic and therapeutic target in cancer: insights and challenges.Frontiers in oncology · 2025Review
- Novel Celecoxib Derivative, RF26, Blocks Colon Cancer Cell Growth by Inhibiting PDE5, Activating cGMP/PKG Signaling, and Suppressing β-catenin-dependent Transcription.Anti-cancer agents in medicinal chemistry · 2025Article
- Blocking the WNT/β-catenin pathway in cancer treatment:pharmacological targets and drug therapeutic potential.Heliyon · 2024Review
- Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health.Frontiers in endocrinology · 2024Review
- Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Functional Axis of PDE5/cGMP Mediates Timosaponin-AIII-Elicited Growth Suppression of Glioblastoma U87MG Cells.Molecules (Basel, Switzerland) · 2023Article
- Article
- Type-2 cGMP-dependent protein kinase suppresses proliferation and carcinogenesis in the colon epithelium.Carcinogenesis · 2022Article
- A novel sulindac derivative protects against oxidative damage by a cyclooxygenase-independent mechanism.The Journal of pharmacology and experimental therapeutics · 2022Article
- NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase.International journal of molecular sciences · 2022Review
- Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer.International journal of molecular sciences · 2021Review
- Suppression of Colon Tumorigenesis in MutantCancer prevention research (Philadelphia, Pa.) · 2021Article
- Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy.Cancers · 2021Review
- New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil.Frontiers in oncology · 2021Review
- Identification of metabolism-associated genes and construction of a prognostic signature in bladder cancer.Cancer cell international · 2020Article
- Sildenafil triggers tumor lethality through altered expression of HSP90 and degradation of PKD2.Carcinogenesis · 2020Article
- PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.Drug discovery today · 2020Review
6 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide (SS) display promising antineoplastic properties, but toxicities resulting from COX inhibition limit their clinical use. Although COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cyclic guanosine monophosphate (cGMP) signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction, factors that influence sensitivity of tumor cells to SS, and the importance of PDE5 for breast tumor cell growth have not been established. Here we show that SS can induce apoptosis of breast tumor cells, which predominantly rely on PDE5 for cGMP hydrolysis but not normal mammary epithelial cells, which rely on PDE isozymes other than PDE5 for cGMP hydrolysis. Inhibition of PDE5 and activation of protein kinase G (PKG) by SS was associated with increased β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased T-cell factor/lymphoid enhancer factor (Tcf/Lef) promoter activity, and decreased expression of Wnt/β-catenin-regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-catenin-mediated transcription in breast tumor cells with minimal effects on normal mammary epithelial cells. These findings provide evidence that SS induces apoptosis of breast tumor cells through a mechanism involving inhibition of PDE5 and attenuation of oncogenic Wnt/β-catenin-mediated transcription. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.