Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate

Sundar, Santhanam; Dickinson, P.

doi:10.1136/bcr.11.2011.5238

Cited by 33 publications

(17 citation statements)

References 12 publications

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“…Consistently, mineralocorticoids such as corticosterone and deoxycorticosterone have been shown to inhibit cell proliferation in androgen‐dependent cells such as LAPC‐4 and LNCaP in the presence of androgens, while MR antagonists such as spironolactone and eplerenone increased LNCaP cell viability . Actually, cases that antagonist of MR spironolactone promoted resistance to AR‐targeting therapies have been reported …”

Section: Discussionmentioning

confidence: 83%

“…17 Actually, cases that antagonist of MR spironolactone promoted resistance to AR-targeting therapies have been reported. 18,19 Mineralocorticoids such as corticosterone and deoxycorticosterone have been shown to inhibit AR activity in the presence of androgens. 16 suggesting an antagonistic activity to AR.…”

Section: The Above Clinical Finding Was Supported By In Vitro Experimmentioning

confidence: 99%

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Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide

et al. 2018

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Section: Discussionmentioning

confidence: 83%

Section: The Above Clinical Finding Was Supported By In Vitro Experimmentioning

confidence: 99%

Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide

et al. 2018

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“…If confirmed, further exploration of the possible effects of spironolactone in the primary prevention of prostate cancer and its place, if any, in the treatment of early stage prostate cancer (currently often managed by active surveillance) and effects on overall mortality in prostate cancer in randomised controlled clinical trials would then be needed before its use could be recommended. Investigation of whether it might accelerate the progression of advanced prostate cancer, as reported in a case study in a single patient , would also be required. In summary, this study identified no increased risk of cancers in people exposed to spironolactone.…”

Section: Discussionmentioning

confidence: 99%

Spironolactone use and risk of incident cancers: a retrospective, matched cohort study

Mackenzie

Morant

Wei

et al. 2016

Brit J Clinical Pharma

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AimsSpironolactone is widely used to treat heart failure, hypertension and liver disease with increased usage in recent years. Spironolactone has endocrine effects that could influence cancer risks and historical reports suggest possible links with increased risk of certain types of cancer. The aim of this study was to assess the effect of spironolactone exposure on cancer incidence.MethodsA pharmacoepidemiological propensity score‐matched cohort study was performed to assess the effect of spironolactone exposure on cancer incidence. Cox proportional hazards models were used to analyse time to first diagnosis of each prespecified cancer and hazard ratios for spironolactone exposure are presented. The setting for the study was UK primary care using the Clinical Practice Research Datalink. The participants were 74 272 patients exposed to spironolactone between 1986 and 2013, matched 1:2 with unexposed controls. The prespecified primary outcomes were the first incidence of ovarian, endometrial, pancreatic, colorectal, prostate, renal cell, pharyngeal and thyroid cancers, and myelomonoblastic/‐cytic leukaemias. Secondary outcomes were the remaining 27 types of cancer.ResultsThere was no evidence of an increased risk of any cancer associated with spironolactone use. Spironolactone use was associated with a significantly lower risk of prostate cancer (hazard ratio 0.69; 95% confidence interval 0.60–0.80, P < 0.001).ConclusionsIn this study, spironolactone use was associated with a lower incidence of prostate cancer, the most common cancer in men in the UK. The possible mechanisms and clinical implications merit further investigation.

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“…The alternative option is to use abiraterone acetate alone and treat patients who develop mineralocorticoid excess with a MRA. However, spironolactone, the first-generation, cheapest and most readily available (competitive) MRA binds to the AR as a mixed agonist/antagonist and could lead to disease progression 34,35 . Eplerenone, a second-generation MRA was developed as a more selective MRA that does not bind wild-type AR but can activate AR mutations previously detected in prostate cancer 23 .…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer

Ferraldeschi

Sharifi

Auchus

et al. 2013

Clinical Cancer Research

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A significant proportion of castration-resistant prostate cancers (CRPC) remain driven by ligand activation of the androgen receptor. Although the testes are the primary source of testosterone, testosterone can also be produced from peripheral conversion of adrenal sex hormone precursors dehydroepiandrosterone (DHEA) and androstenedione (AD) in the prostate and other tissues. CYP17A1 catalyzes two essential reactions in the production of DHEA and androstenedione: the hydroxylation (hydroxylase activity) and the subsequent cleavage of the C17-20 side-chain (lyase activity). Potent and selective inhibition of CYP17A1 by abiraterone depletes residual non-gonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform on the development of novel therapeutic strategies post abiraterone. Preclinical evidence that androgen biosynthesis in prostate cancer cells does not necessarily follow a single dominant pathway and residual androgens or alternative ligands (including administered glucocorticoids) can reactivate androgen receptor signaling supports co-targeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an anti-androgen. Furthermore, given the drawbacks of 17α-hydroxylase inhibition, there is considerable interest in developing new CYP17A1 inhibitors that more specifically inhibit lyase activity and are therefore less likely to require glucocorticoid co-administration.

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Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate

Cited by 33 publications

References 12 publications

Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide

Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide

Spironolactone use and risk of incident cancers: a retrospective, matched cohort study

Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer

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