Investigational noncardiovascular uses of phosphodiesterase-5 inhibitors

Kloner, Robert A.; Comstock, Gary; Levine, Laurence A.; Tiger, Steven; Stecher, Vera J.

doi:10.1517/14656566.2011.600306

Cited by 13 publications

(11 citation statements)

References 112 publications

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“…However, due to their favorable toxicity profile (44), these agents are being investigated in a wide range of other potential medical and surgical applications, including neurologic and cardiovascular disorders, transplant and reconstructive surgery, and several clinical trials are currently in progress (15). In the last ten years, various PDE5 inhibitors have been also reported to inhibit growth and induce apoptosis in many cancer cell lines, without affecting normal epithelial cells (12-14, 16, 18, 19).…”

Section: Discussionmentioning

confidence: 99%

“…In the last ten years, overexpression of PDE5 has been described in multiple human carcinomas, including bladder, lung, and breast cancers (10)(11)(12)(13). The increased expression of PDE5 in human malignancies coupled with the efficacy and high tolerability profiles of PDE5 inhibitors (i.e., sildenafil and vardenafil) in the treatment of erectile dysfunction and pulmonary hypertension have led to an increased interest in investigating PDE5-targeted drugs in cancer management (14,15). Indeed, several in vitro observations have shown antiproliferative and proapoptotic effects of PDE5 inhibitors in cancer cell lines, as those of the breast (13,14,16,17).…”

Section: Introductionmentioning

confidence: 99%

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Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

Catalano

Campana

Giordano

et al. 2016

Clinical Cancer Research

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Purpose: By catalyzing cGMP hydrolysis, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and effects in different (patho)physiologic processes, including cancers. As PDE5 is a known druggable target, we investigated the clinical significance of its expression in breast cancer and the underlying mechanisms by which it may contribute to tumor progression.Experimental Design: PDE5 expression was evaluated in seven breast cancer cell lines by RT-PCR and immunoblotting. To examine the impact of PDE5 on cancer phenotype, MCF-7 cells expressing lower levels of the enzyme were engineered to stably overexpress PDE5. Proliferation was evaluated by MTT assays, motility and invasion by wound-healing/transmigration/invasion assays, transcriptome-profiling by RNA-sequencing, and Rho GTPase signaling activation by GST-pulldown assays and immunoblotting. Clinical relevance was investigated by IHC on tissues and retrospective studies from METABRIC cohort.Results: PDE5 is differentially expressed in each molecular subtype of both breast cancer cell lines and tissues, with higher levels representing a startling feature of HER2-positive and triplenegative breast cancers. A positive correlation was established between elevated PDE5 levels and cancers of high histologic grade. Higher PDE5 expression correlated with shorter patient survival in retrospective analyses. On molecular level, stable PDE5 overexpression in Luminal-A-like MCF-7 cells resulted in enhanced motility and invasion through Rho GTPase signaling activation. Treatment of PDE5-stable clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control vector cells.Conclusions: PDE5 expression enhances breast cancer cell invasive potential, highlighting this enzyme as a novel prognostic candidate and an attractive target for future therapy in breast cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

Catalano

Campana

Giordano

et al. 2016

Clinical Cancer Research

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“…As recently reviewed by Kloner and colleagues (Kloner et al, 2011), in addition to the well-defined vascular protective effects of PDE5 inhibitors in non-diabetic conditions (Aversa et al, 2007; Mazo et al, 2006; Rosano et al, 2005), several pre-clinical and clinical studies have also focused on the effects of PDE5 inhibitors on arterial endothelium, which is adversely affected by hyperglycemia in type 2 diabetes (T2D). Based on a possible link between painful neuropathy and insufficient NO synthesis under diabetic conditions, PDE5 inhibitors have been tested for prevention of diabetic neuropathy and vasculopathy.…”

Section: Pde5 Inhibitors In Diabetesmentioning

confidence: 99%

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

Das

Durrant

Salloum

et al. 2015

Pharmacology & Therapeutics

192

150

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The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and cancer benefits. Despite mixed results of these clinical trials, there is continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients.

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“…5 Several PDE5 inhibitors are being developed for lower urinary tract symptoms secondary to benign prostatic hyperplasia. 6 Thus, PDE5 participates in the regulation of many physiological functions.…”

mentioning

confidence: 99%

Avanafil, a Potent and Highly Selective Phosphodiesterase-5 Inhibitor for Erectile Dysfunction

Kotera¹,

Mochida²,

Inoue³

et al. 2012

Journal of Urology

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Investigational noncardiovascular uses of phosphodiesterase-5 inhibitors

Abstract: The exceptionally wide range of research taking place with PDE5 inhibitors holds promise not only for improved therapeutic options but also for an improved understanding of the basic biological mechanisms that underlie scientific medicine.

Cited by 13 publications

References 112 publications

Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

Avanafil, a Potent and Highly Selective Phosphodiesterase-5 Inhibitor for Erectile Dysfunction

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