Amiloride Is Effective in the Management of Abiraterone-Induced Mineralocorticoid Excess Syndrome without Interfering with Its Antineoplastic Activity

Abstract

Background: The administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES). Methods: The efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC). Then, using the in vitro experimental model of PCa cell lines, the possible effects of drugs usually used in the clinical management of CRPC patients on PCa cell viability were investigated. Results: Amiloride/HCT led to a complete disappearance of all clinical and biochemical signs of abiraterone-induced MCES in the 5 treated patients. The in vitro study showed that abiraterone treatment significantly decreased cell viability of both androgen receptor (AR)-expressing VCaP (vertebral-cancer of the prostate) and LNCaP (lymph node carcinoma of the prostate) cells, with no effect on AR-negative PC-3 cells. Prednisolone, spironolactone, and eplerenone increased LNCaP cell viability, while amiloride reduced it. The non-steroid aldosterone antagonist PF-03882845 did not modify PCa cell viability. Conclusions: The combination of amiloride/HCT was effective in the management of abiraterone-induced MCES. Amiloride did not negatively interfere with the abiraterone inhibition of PCa cell viability in vitro.

The Role of Mineralocorticoid Receptor Signaling in Genitourinary Cancers

“…In contrast to epidemiological evidence described above [33], MR antagonists, including spironolactone and eplerenone, were shown to induce the proliferation of ARdependent LNCaP prostate cancer cells, while a non-steroidal antagonist PF-03882845 had no significant effects on their growth [36]. Additionally, in prostate cancer xenograftbearing mice resistant to the treatment with an ERG inhibitor, the expression of the MR and its target genes, such as FKBP5, SGK1, TNS1, and TSC22D3, was significantly up-regulated [37].…”

Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide

“…Meanwhile, MR knockdown augmented cellular resistance to enzalutamide, supporting the mineralocorticoid effect via MR. 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 …”

“…that pure glucocorticoid dexamethasone augmented cellular shown to inhibit cell proliferation in androgen-dependent cells such as LAPC-4 and LNCaP in the presence of androgens, 16 while MR antagonists such as spironolactone and eplerenone increased LNCaP cell viability. 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.…”

The Role of Nuclear Receptors in Prostate Cancer

“…In addition, MR suppression by siRNA or antagonists such as spironolactone and eplerenone have been shown to activate AR signaling, suggesting an antagonistic activity to AR [130,131]. Consistent with these findings, mineralocorticoids such as corticosterone and deoxycorticosterone inhibited cell proliferation in androgen-dependent LAPC-4 and LNCaP cells in the presence of androgens [129], while MR antagonists increased LNCaP cell viability [132]. Moreover, MR signaling augmented cellular sensitivity to the antiandrogen enzalutamide [131].…”