Thromboxane A2 [TxA2]

[pjoshea13]

New study from Spain below [1].

PCa cells tend to have elevated levels of the omega-6 fatty acid: Arachidonic Acid [AA]. NF-kB, which is chronically activated in PCa creates numerous cell-survival proteins, includin the COX enzymes. Acting on AA, COX-2 creates prostaglandins and thromboxane [Tx] (TXA2 is generated from prostaglandin H2). TxA2 has a significant role in PCa cell motility.

The oldest PubMed hit for <prostate "thromboxane A2">is from Sweden (1989) [2].

"Twenty patients with prostatic carcinoma were randomized to therapy with either oestrogens (n = 10) or orchidectomy (n = 10)." {Did the men know which arm they were assigned to? In mice studies, sham surgery is not uncommon.]

"... patients with prostatic cancer during long-term oestrogen treatment were found to have increased levels of factor VII, factor VIII:C and fibrinogen. In addition these patients showed increased formation of thromboxane. The changes imply a hypercoaguable state and platelet activation. No such signs were found after orchidectomy. The findings in the oestrogen group might explain the continuously increased risk of cardiovascular complications during long-term oestrogen therapy."

{Will raise some eyebrows in those following the PATCH trial.}

U.S. (2005) [3]:

"Castration reduces platelet thromboxane A2 receptor density and aggregability"

"We studied surgically and/or medically castrated men with prostate cancer (group A, n = 8, aged 71 +/- 8 years) and age-matched, uncastrated urology patients (group B, n = 7, aged 67 +/- 9 years)."

"Group A had significantly lower plasma testosterone than group B (16 +/- 5 ng/dl vs. 308 +/- 47 ng/dl ...)"

"Platelet TXA2 receptor density (B(max)) ... was lower in group A (0.50 +/- 0.12 vs. 1.01 +/- 0.17 pmol/mg protein ...)"

Belgium (2006) [4]:

"Proteins specifically involved in the TXA(2) pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation. Our study is the first to examine simultaneously all key proteins involved in this pathway including TXA(2) receptors and results suggest that the TXA(2) pathway may be a potential target for PCa prevention/therapy."

From the new study [1]:

"The serum level of TXA2 in patients with PCa was increased with respect to healthy subjects, which was further increased by ADT."

"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."

One could consider a selective COX-2 inhinitor [Celecoxib - Celebrex - which is not recommended for those with a high risk of heart disease.] Or, one could load-up on natural polyphenols that are all anti-inflammatory & NF-kB inhibitors. Mix & match the usual suspects & check serum markers of inflammation.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/339...

Front Cardiovasc Med

. 2021 Apr 13;8:653126. doi: 10.3389/fcvm.2021.653126. eCollection 2021.

Androgen Deprivation Therapy in Patients With Prostate Cancer Increases Serum Levels of Thromboxane A 2: Cardiovascular Implications

Mario Álvarez-Maestro 1 2 , Aritz Eguibar 1 , Patricia Chanca 3 , Mercedes Klett-Mingo 4 , Juan Gómez Rivas 5 , Antonio Buño-Soto 3 6 , Fermín R de Bethencourt 1 2 , Mercedes Ferrer 2 4

Affiliations expand

PMID: 33928136 PMCID: PMC8076684 DOI: 10.3389/fcvm.2021.653126

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.

Copyright © 2021 Álvarez-Maestro, Eguibar, Chanca, Klett-Mingo, Gómez Rivas, Buño-Soto, de Bethencourt and Ferrer.

[2] pubmed.ncbi.nlm.nih.gov/251...

[3] pubmed.ncbi.nlm.nih.gov/158...

[4] pubmed.ncbi.nlm.nih.gov/165...

[cesces]

"

PCa cells tend to have elevated levels of the omega-6 fatty acid: Arachidonic Acid [AA]. NF-kB, which is chronically activated in PCa creates numerous cell-survival proteins, includin the COX enzymes. "

What is a cell survival protein?

Why would that not be a good thing?

[pjoshea13 in reply to cesces]

PCa uses/abuses the same pathways as normal cells under viral/bacterial assault, but they were not intended for chronic use.

More info: people.bu.edu/gilmore/nf-kb...

[MateoBeach]

Thanks for this important overview on thromboxane A2. Phospholipase -C feeds the adverse fatty acid Arachidonic acid via cycloxygenase into both prostaglandins and to thromboxane A2. I use celecoxib 400 mg/day to inhibit COX2 and reduce inflammation. And also low dose ASA. Apparently Naproxen even in high doses can block thromboxane A2 effectively with no increased cardiovascular risk. ( Unlike any other COX1 NSAID.)

Not sure if the early estrogen data is applicable to E2 patch use vs oral, which we know has high risk.

Currently, I am trying to intuit a reasonable strategy for my intermittent use of high dose testosterone. Alternate or with being simply off hormonal treatment vs. with ADT (Firmagon plus estradiol?) or enzalutamide mono therapy cycles?

And how many months between one month SPT cycles. My inclination (per adaptive therapy) is to keep mixing things up. Sure do like high T vs. ADT though! 💪💪😛

You place your bets and spin the wheel. ..