Androgen Deprivation Therapy in Patients With Prostate Cancer Increases Serum Levels of Thromboxane A2: Cardiovascular Implications

Mario Álvarez-Maestro; Aritz Eguibar; Patricia Chanca; Mercedes Klett-Mingo; Juan Gómez Rivas; Antonio Buño-Soto; Fermín R de Bethencourt; Mercedes Ferrer

doi:10.3389/fcvm.2021.653126

Androgen Deprivation Therapy in Patients With Prostate Cancer Increases Serum Levels of Thromboxane A₂: Cardiovascular Implications

Front Cardiovasc Med. 2021 Apr 13:8:653126. doi: 10.3389/fcvm.2021.653126. eCollection 2021.

Authors

Mario Álvarez-Maestro^{1

2}, Aritz Eguibar¹, Patricia Chanca³, Mercedes Klett-Mingo⁴, Juan Gómez Rivas⁵, Antonio Buño-Soto^{3

6}, Fermín R de Bethencourt^{1

2}, Mercedes Ferrer^{2

4}

Affiliations

¹ Servicio de Urología, Hospital Universitario La Paz, Madrid, Spain.
² Grupo de Investigación en Urología, IdiPAZ, Madrid, Spain.
³ Servicio de Análisis Clínicos, Hospital Universitario La Paz, Madrid, Spain.
⁴ Departamento de Fisiología, Facultad de Medicina, UAM, Madrid, Spain.
⁵ Departamento de Urología, Hospital Clínico San Carlos, Madrid, Spain.
⁶ Grupo de Investigación en Neonatología, IdiPAZ, Madrid, Spain.

Abstract

Introduction: Androgens have been described as important players in the regulation of vascular function/structure through their action on the release and effect of vasoactive factors, such as prostanoids. Patients with prostate cancer (PCa) under androgen deprivation therapies (ADTs) present increased risk of cardiovascular mortality. Since thromboxane A₂ (TXA₂) is one of the most studied prostanoids and its involvement in different cardiovascular diseases has been described, the aim of this study was to investigate: (i) the effect of ADT on the serum levels of TXA₂ in PCa patients and its possible link to the redox status and (ii) the effect of the non-hydrolyzable TXA₂ analog U-46619 on the function of the aorta of male rats. Methods: The levels of TXA₂ and total antioxidant status in 50 healthy subjects, 54 PCa patients, and 57 PCa under ADT were evaluated. These determinations were accompanied by levels of testosterone and C-reactive protein as an inflammation marker. In aortic segments from male rats, the U46619-induced effects on: (i) the vasomotor responses to acetylcholine (ACh), to the NO donor sodium nitroprusside (SNP), to the carbon monoxide-releasing molecule-3 (CORM-3), and to noradrenaline (NA) and (ii) the expression of cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), and phosphorylated ERK1/2 were analyzed. Results: The serum level of TXA₂ in patients with PCa was increased with respect to healthy subjects, which was further increased by ADT. There was no modification in the total antioxidant status among the three experimental groups. In aortic segments from male rats, the TXA₂ analog decreased the endothelium-dependent relaxation and the sensitivity of smooth muscle cells to NO, while it increased the vasoconstriction induced by NA; the expression of COX-2, HO-1, and pERK1/2 was also increased. Conclusions: ADT increased, along with other inflammatory/oxidative markers, the serum levels of TXA₂. The fact that TXA₂ negatively impacts the vascular function of the aorta of healthy male rats suggests that inhibition of TXA₂-mediated events could be considered a potential strategy to protect the cardiovascular system.

Keywords: androgen deprivation therapy (ADT); endothelium; prostate cancer; thromboxane A2 (TXA2); vascular function.