Cargando…
Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer
Prostate cancer (PCa) growth and progression rely on the interaction between the androgen receptor (AR) and the testicular ligands, testosterone and dihydrotestosterone (DHT). Almost all men with advanced PCa receive androgen deprivation therapy (ADT). ADT lowers circulating testosterone levels, whi...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Second Military Medical University
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363635/ https://www.ncbi.nlm.nih.gov/pubmed/30775248 http://dx.doi.org/10.1016/j.ajur.2018.09.002 |
_version_ | 1783393135008677888 |
---|---|
author | Fiandalo, Michael V. Gewirth, Daniel T. Mohler, James L. |
author_facet | Fiandalo, Michael V. Gewirth, Daniel T. Mohler, James L. |
author_sort | Fiandalo, Michael V. |
collection | PubMed |
description | Prostate cancer (PCa) growth and progression rely on the interaction between the androgen receptor (AR) and the testicular ligands, testosterone and dihydrotestosterone (DHT). Almost all men with advanced PCa receive androgen deprivation therapy (ADT). ADT lowers circulating testosterone levels, which impairs AR activation and leads to PCa regression. However, ADT is palliative and PCa recurs as castration-recurrent/resistant PCa (CRPC). One mechanism for PCa recurrence relies on intratumoral synthesis of DHT, which can be synthesized using the frontdoor or primary or secondary backdoor pathway. Androgen metabolism inhibitors, such as those targeting 5α-reductase, aldo-keto-reductase family member 3 (AKR1C3), or cytochrome P450 17A1 (CYP17A1) have either failed or produced only modest clinical outcomes. The goal of this review is to describe the therapeutic potential of combined inhibition of 5α-reductase and 3α-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis. Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation. |
format | Online Article Text |
id | pubmed-6363635 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Second Military Medical University |
record_format | MEDLINE/PubMed |
spelling | pubmed-63636352019-02-15 Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer Fiandalo, Michael V. Gewirth, Daniel T. Mohler, James L. Asian J Urol Review Prostate cancer (PCa) growth and progression rely on the interaction between the androgen receptor (AR) and the testicular ligands, testosterone and dihydrotestosterone (DHT). Almost all men with advanced PCa receive androgen deprivation therapy (ADT). ADT lowers circulating testosterone levels, which impairs AR activation and leads to PCa regression. However, ADT is palliative and PCa recurs as castration-recurrent/resistant PCa (CRPC). One mechanism for PCa recurrence relies on intratumoral synthesis of DHT, which can be synthesized using the frontdoor or primary or secondary backdoor pathway. Androgen metabolism inhibitors, such as those targeting 5α-reductase, aldo-keto-reductase family member 3 (AKR1C3), or cytochrome P450 17A1 (CYP17A1) have either failed or produced only modest clinical outcomes. The goal of this review is to describe the therapeutic potential of combined inhibition of 5α-reductase and 3α-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis. Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation. Second Military Medical University 2019-01 2018-09-26 /pmc/articles/PMC6363635/ /pubmed/30775248 http://dx.doi.org/10.1016/j.ajur.2018.09.002 Text en © 2019 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Review Fiandalo, Michael V. Gewirth, Daniel T. Mohler, James L. Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer |
title | Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer |
title_full | Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer |
title_fullStr | Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer |
title_full_unstemmed | Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer |
title_short | Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer |
title_sort | potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363635/ https://www.ncbi.nlm.nih.gov/pubmed/30775248 http://dx.doi.org/10.1016/j.ajur.2018.09.002 |
work_keys_str_mv | AT fiandalomichaelv potentialimpactofcombinedinhibitionof3aoxidoreductasesand5areductasesonprostatecancer AT gewirthdanielt potentialimpactofcombinedinhibitionof3aoxidoreductasesand5areductasesonprostatecancer AT mohlerjamesl potentialimpactofcombinedinhibitionof3aoxidoreductasesand5areductasesonprostatecancer |