Novel 5α‐steroid reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer

  title={Novel 5$\alpha$‐steroid reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer},
  author={Motohide Uemura and Kenji Tamura and Suyoun Chung and Seijiro Honma and Akihiko Okuyama and Yusuke Nakamura and Hidewaki Nakagawa},
  journal={Cancer Science},
Prostate cancer often relapses during androgen‐depletion therapy, even under conditions in which a drastic reduction of circulating androgens is observed. There is some evidence that androgens remain present in the tissues of hormone‐refractory prostate cancers (HRPC), and enzymes involved in the androgen and steroid metabolic pathway are likely to be active in HRPC cells. We previously carried out a genome‐wide gene expression profile analysis of clinical HRPC cells by means of cDNA… 

5αDH‐DOC (5α‐dihydro‐deoxycorticosterone) activates androgen receptor in castration‐resistant prostate cancer

Findings implicated that under an extremely low level of DHT, 5αDH‐DOC and other products of 5α‐steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.

Androgen Regulation of 5α-Reductase Isoenzymes in Prostate Cancer: Implications for Prostate Cancer Prevention

It is found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type–specific manner, that regulation occurs at the transcriptional level, and that AR is necessary for this regulation.

Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer

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 coadministration.

Potential Prostate Cancer Drug Target: Bioactivation of Androstanediol by Conversion to Dihydrotestosterone

Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone–releasing hormone agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate).

Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer.

Analysis of androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients indicated that patients with TMPRSS2-ERG-positive prostate cancer may benefit from novel inhibitors targeting the alternative DHT biosynthesis.

In silico structural prediction of human steroid 5α-reductase type II

A comparative structure of 5α-reductase type II was illustrated that derived from the homology modeling, employing a membrane-bound protein, isoprenylcysteine carboxyl methyltransferase as a homologous template, and depicted the well-defined comparative three-dimensional structure applicable for steroid reductase drug design.

Synthesis and Identification of Pregnenolone Derivatives as Inhibitors of Isozymes of 5α‐Reductase

The results indicate that of the five steroids studied, the 21(p‐fluoro)benzoyloxypregna‐4,16‐diene‐3,6,20‐trione derivative has the best molecular conformation to inhibit the in vitro activity of both types of 5α‐R.

Targeting 5α-reductase for prostate cancer prevention and treatment

The two largest trials to investigate the use of the 5α-reductase inhibitors (5ARIs) finasteride and dutasteride in patients with prostate cancer have shown that, although the incidence of cancer was reduced by 5ARI treatment, those cancers that were detected were more aggressive than in patients treated with placebo.



The Adrenal Androgen Androstenediol Is Present in Prostate Cancer Tissue after Androgen Deprivation Therapy and Activates Mutated Androgen Receptor

It is found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy, and this results indicate thatadiol may cause the progression of PCa even after hormone therapy.

Decreased gene expression of steroid 5 alpha‐reductase 2 in human prostate cancer: Implications for finasteride therapy of prostate carcinoma

The therapeutic influence of SRD5A2 inhibitor finasteride on prostate cancer is currently unknown and the direction and extent of changes in SRD4A2 expression in disease tissues is a relevant issue.

Steroid 5α-Reductase Isozymes I and II in Recurrent Prostate Cancer

It was shown that recurrent prostate cancer tissue has testosterone levels similar to androgen-stimulated benign prostate, whereas dihydrotestosterone levels were reduced 82% to 1.45 nmol/L, sufficient for androgen receptor activation, suggesting loss of 5α-reducing capability.

Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor

It is shown that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr), demonstrating a previously unknown mechanism for the androgen-independent growth of advanced CaP.

Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer.

It is suggested that short-term treatment with dutasteride can cause regression in some prostate cancers, and dual inhibition of both isoenzymes may be more effective than suppression of 5alphaR2 alone in prostate cancer treatment or prevention.

Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis.

  • H. ScherC. Sawyers
  • Biology, Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2005
Strategies that are focused on the androgen receptor either directly or indirectly, as single agents or in combination, that are in clinical development that are discussed are discussed.

Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia

A more effective dual inhibitor of type 1 and 2 human 5α-reductase may lower circulating dihydrotestosterone to a greater extent than finasteride and show advantages in treating human benign prostatic hyperplasia and other disease states that depend on dihydotestosterone.

Dihydrotestosterone and the Concept of 5α–Reductase Inhibition in Human Benign Prostatic Hyperplasia

Clinical evaluation of potent dual 5α–reductase inhibitors may help define the relative roles of human type 1 and 2 5α-reduct enzyme in the pathophysiology of benign prostatic hyperplasia and other androgen–dependent diseases.

Natural mutagenesis study of the human steroid 5α-reductase 2 isozyme

Nine additional mutations in the 5alpha-reductase 2 gene in subjects with 5 alpha- reductase deficiency are described, providing insight into functional domains in the protein as well as an unusual acidic pH optimum characteristic of the 5Alpha-Reductase type 2 isozyme.