The Association Between Phosphodiesterase-5 Inhibitors and Colorectal Cancer in a National Cohort of Patients

Sutton, S Scott; Magagnoli, Joseph; Cummings, Tammy H.; Hardin, James W.

doi:10.14309/ctg.0000000000000173

Cited by 18 publications

(22 citation statements)

References 24 publications

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“…A large body of work spanning two decades has highlighted cGMP-elevating PDE inhibitors for the prevention and treatment of colorectal cancer. Building on this foundation, recent largecohort retrospective epidemiological studies support their efficacy in humans, and provide the impetus for prospective clinical studies to interrogate their utility in patients (Huang et al, 2019;Sutton et al, 2020). However, there are inconsistencies in the literature regarding the potential utility of cGMP-PDE inhibitors as a primary prevention modality or as chemotherapy for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Colon Cancer Cell Growth by Phosphodiesterase Inhibitors Is Independent of cGMP Signaling

Hou

Wren

Mylarapu

et al. 2022

J Pharmacol Exp Ther

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There is growing interest in the potential use of phosphodiesterase (PDE) inhibitors for colorectal cancer (CRC) prevention and treatment. The present study has tested the idea that PDE inhibitors inhibit growth and viability of CRC cell lines by increasing cyclic guanosine monophosphate (cGMP) and activating cGMP-dependent protein kinase (PKG). Colon cancer cell lines and those with ectopic PKG2 expression were treated with membrane permeable 8Br-cGMP or inhibitors of PDE5, 9, 10a. Levels of cGMP capable of activating PKG were measured by immunoblotting for phosphorylation of vasodilator-stimulated phosphoprotein (VASP). The effects of treatment on CRC cell proliferation and death were measured using hemocytometry with trypan blue. Treatment with 8Br-cGMP had no effect on CRC cell proliferation or death.Endogenous PKG activity was undetectable in any of the CRC cells, but expression of ectopic PKG2 conferred modest inhibition of proliferation but did not affect cell death. Extremely high concentrations of all the PDE inhibitors reduced proliferation in CRC cell lines, but none of them increased cGMP levels, and the effect was independent of PKG expression. The inability of the PDE inhibitors to increase cGMP was due to the lack of endogenous cGMP generating machinery. In conclusion, PDE inhibitors that target cGMP only reduce CRC growth at clinically unachievable concentrations, and do so independent of cGMP signaling through PKG.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Colon Cancer Cell Growth by Phosphodiesterase Inhibitors Is Independent of cGMP Signaling

Hou

Wren

Mylarapu

et al. 2022

J Pharmacol Exp Ther

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“…PDE5 inhibitor use was associated with a significantly lower incidence of CRC (Figure 3; OR 0.85, CI 0.78–0.93, p < 0.001, I 2 = 52%). Three studies comprised 88.1% of the overall weighting of effect [22, 25, 35].…”

Section: Resultsmentioning

confidence: 99%

The protective role of phosphodiesterase inhibitors in preventing colorectal cancer and advanced colorectal polyps: a systematic review and meta‐analysis

Cullinane,

Brett,

Devane

et al. 2023

Colorectal Disease

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AimInflammatory cells within the tumour microenvironment are the driving forces behind colorectal cancer (CRC) tumourigenesis. Understanding the different pathways involved in CRC carcinogenesis paves the way for effective repurposing of drugs for cancer prevention. Emerging data from preclinical and clinical studies suggest that, due to their antiproliferative and anti‐inflammatory properties, phosphodiesterase‐5 inhibitors (PDE5i) might have an anticancer effect. The aim of this study was to clarify through systematic review and meta‐analysis of published peer‐reviewed studies whether an association exists between PDE5i use and CRC risk.MethodThis study was guided by the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Prospective registration was performed on PROSPERO (CRD42022372925). A systematic review was performed for studies reporting CRC and advanced colorectal polyp incidence in PDE5i ‘ever‐users’ and PDE5i ‘never‐users’. Meta‐analysis was performed using RevMan version 5.ResultsFour observational cohort studies and two case–control studies, comprising 995 242 patients were included in the final analysis, of whom 347 126 were PDE5i ever‐users. Patients who were PDE5i ever‐users had a significantly lower incidence of CRC or advanced colorectal polyps than never‐users (OR 0.88, CI 0.79–0.98, p = 0.02). To examine the primary preventative role of PDE5i, subgroup analysis of four studies including patients without a previous history of CRC found that use of PDE5i was associated with a lower incidence of CRC (OR 0.85, CI 0.75–0.95, p = 0.005, I2 = 64%). There was no significant temporal relationship found between PDE5i use and CRC risk as both current users and previous users had a significantly lower incidence of CRC than never‐users.ConclusionOur study found a significant anticancer effect of PDE5i, as shown by a reduced risk of CRC in the context of both primary and secondary CRC prevention.

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“…Besides, polyps formed in sildenafil-treated mice showed greater differentiation, less proliferation, less inflammation, little infiltration of myeloid cells as well as a reduction in the expression of pro-inflammatory factors such as INFg and IL-6 (71). In a study of 192,661 patients, the use of PDE5 inhibitors was shown to be associated with a decreased risk of developing colon cancer (72).…”

Section: Colorectal Cancermentioning

confidence: 99%

New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil

et al. 2021

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The use of already-approved drugs to treat new or alternative diseases has proved to be beneficial in medicine, because it reduces both drug development costs and timelines. Most drugs can be used to treat different illnesses, due their mechanisms of action are not restricted to one molecular target, organ or illness. Diverging from its original intent offers an opportunity to repurpose previously approved drugs to treat other ailments. This is the case of sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor, which was originally designed to treat systemic hypertension and angina but is currently commercialized as erectile dysfunction treatment. Sildenafil, tadalafil, and vardenafil are PDE5 inhibitors and potent vasodilators, that extend the physiological effects of nitric oxide and cyclic guanosine monophosphate (cGMP) signaling. Although most of the biological implications of these signaling regulations remain unknown, they offer a large therapeutic potential for several diseases. In addition, some PDE5 inhibitors’ molecular effects seem to play a key role in different illnesses such as kidney disease, diabetes mellitus, and cancer. In this review, we discuss the molecular effects of PDE5 inhibitors and their therapeutic repurposing in different types of cancer.

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The Association Between Phosphodiesterase-5 Inhibitors and Colorectal Cancer in a National Cohort of Patients

Cited by 18 publications

References 24 publications

Inhibition of Colon Cancer Cell Growth by Phosphodiesterase Inhibitors Is Independent of cGMP Signaling

Inhibition of Colon Cancer Cell Growth by Phosphodiesterase Inhibitors Is Independent of cGMP Signaling

The protective role of phosphodiesterase inhibitors in preventing colorectal cancer and advanced colorectal polyps: a systematic review and meta‐analysis

New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil

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