DHEA & Drug Resistance.

[pjoshea13]

New paper below.

For years they used the term androgen-independant PCa. Then they realized that the androgen receptor was still in play, & that castration didn't go far enough. We thought that Zytiga took care of the adrenal problem, but now:

"DHEA is a product of the P450c17 (17α-hydroxylase-17,20-lyase) enzyme. Despite inhibition of P450c17 with new agents, e.g., Abiraterone acetate, Orterenol, and Galeterone, the level of enzyme inhibition rarely exceeds 90% leaving behind a significant depot for androgen biosynthesis within the tumor."

"The depot of DHEA-SO4 that remains after P450c17 inhibition and the adaptive responses that occur within the tumor to promote DHEA utilization contribute to mechanisms of drug resistance observed with P450c17 inhibitors."

What will life be like when all steroid hormones are finally eradicated from the body? Seems that only a total scortched earth campaign will save us.

-Patrick

ncbi.nlm.nih.gov/pubmed/300...

Vitam Horm. 2018;108:309-331. doi: 10.1016/bs.vh.2018.01.007. Epub 2018 Feb 24.

Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer.

Penning TM1.

Author information

1

Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: [e-mail].

Abstract

Dehydroepiandrosterone (DHEA)-SO4 of adrenal origin is the major C19 steroid in the serum. It is a precursor of intratumoral androgen biosynthesis in patients with advanced prostate cancer following chemical or surgical castration. DHEA is a product of the P450c17 (17α-hydroxylase-17,20-lyase) enzyme. Despite inhibition of P450c17 with new agents, e.g., Abiraterone acetate, Orterenol, and Galeterone, the level of enzyme inhibition rarely exceeds 90% leaving behind a significant depot for androgen biosynthesis within the tumor. For DHEA-SO4 to be utilized there is uptake by organic anion transporter polypeptides, deconjugation catalyzed by steroid sulfatase, and adaptive upregulation of prostate steroidogenic enzymes that will convert DHEA into either testosterone or dihydrotestosterone. The depot of DHEA-SO4 that remains after P450c17 inhibition and the adaptive responses that occur within the tumor to promote DHEA utilization contribute to mechanisms of drug resistance observed with P450c17 inhibitors. Knowledge of these mechanisms identify new targets for therapeutics that could be used to surmount drug resistance in prostate cancer.

KEYWORDS:

Androgens; Hydroxysteroid dehydrogenase; Organic anion transporter polypeptides; Prostate cancer; Steroid sulfatase

PMID: 30029732 DOI: 10.1016/bs.vh.2018.01.007