Cargando…
Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells
BACKGROUND: Lysine-specific demethylase 1 (LSD1 or KDM1A) overexpression correlates with poor survival and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling promoting c-MYC expression. We examined the antitumor efficacy of LSD1 inhibiti...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133270/ https://www.ncbi.nlm.nih.gov/pubmed/27349498 http://dx.doi.org/10.1038/pcan.2016.21 |
_version_ | 1782471235344531456 |
---|---|
author | Gupta, S Weston, A Bearrs, J Thode, T Neiss, A Soldi, R Sharma, S |
author_facet | Gupta, S Weston, A Bearrs, J Thode, T Neiss, A Soldi, R Sharma, S |
author_sort | Gupta, S |
collection | PubMed |
description | BACKGROUND: Lysine-specific demethylase 1 (LSD1 or KDM1A) overexpression correlates with poor survival and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling promoting c-MYC expression. We examined the antitumor efficacy of LSD1 inhibition with HCI-2509 in advanced stages of prostate cancer. METHODS: Cell survival, colony formation, histone methylation, c-MYC level, c-MYC expression, cell cycle changes and in vivo efficacy were studied in castration-resistant prostate cancer cells upon treatment with HCI-2509. In vitro combination studies, using HCI-2509 and docetaxel, were performed to assess the synergy. Cell survival, colony formation, histone methylation and c-myc levels were studied in docetaxel-resistant prostate cancer cells treated with HCI-2509. RESULTS: HCI-2509 is cytotoxic and inhibits colony formation in castration-resistant prostate cancer cells. HCI-2509 treatment causes a dose-dependent increase in H3K9me2 (histone H3lysine 9) levels, a decrease in c-MYC protein, inhibition of c-MYC expression and accumulation in the G0/G1 phase of the cell cycle in these cells. PC3 xenografts in mice have a significant reduction in tumor burden upon treatment with HCI-2509 with no associated myelotoxicity or weight loss. More synergy is noted at sub-IC(50) (half-maximal inhibitory concentration) doses of docetaxel and HCI-2509 in PC3 cells than in DU145 cells. HCI-2509 has growth-inhibitory efficacy and decreases the c-myc level in docetaxel-resistant prostate cancer cells. CONCLUSIONS: LSD1 inhibition with HCI-2509 decreases the c-MYC level in poorly differentiated prostate cancer cell lines and has a therapeutic potential in castration- and docetaxel-resistant prostate cancer. |
format | Online Article Text |
id | pubmed-5133270 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51332702016-12-16 Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells Gupta, S Weston, A Bearrs, J Thode, T Neiss, A Soldi, R Sharma, S Prostate Cancer Prostatic Dis Original Article BACKGROUND: Lysine-specific demethylase 1 (LSD1 or KDM1A) overexpression correlates with poor survival and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling promoting c-MYC expression. We examined the antitumor efficacy of LSD1 inhibition with HCI-2509 in advanced stages of prostate cancer. METHODS: Cell survival, colony formation, histone methylation, c-MYC level, c-MYC expression, cell cycle changes and in vivo efficacy were studied in castration-resistant prostate cancer cells upon treatment with HCI-2509. In vitro combination studies, using HCI-2509 and docetaxel, were performed to assess the synergy. Cell survival, colony formation, histone methylation and c-myc levels were studied in docetaxel-resistant prostate cancer cells treated with HCI-2509. RESULTS: HCI-2509 is cytotoxic and inhibits colony formation in castration-resistant prostate cancer cells. HCI-2509 treatment causes a dose-dependent increase in H3K9me2 (histone H3lysine 9) levels, a decrease in c-MYC protein, inhibition of c-MYC expression and accumulation in the G0/G1 phase of the cell cycle in these cells. PC3 xenografts in mice have a significant reduction in tumor burden upon treatment with HCI-2509 with no associated myelotoxicity or weight loss. More synergy is noted at sub-IC(50) (half-maximal inhibitory concentration) doses of docetaxel and HCI-2509 in PC3 cells than in DU145 cells. HCI-2509 has growth-inhibitory efficacy and decreases the c-myc level in docetaxel-resistant prostate cancer cells. CONCLUSIONS: LSD1 inhibition with HCI-2509 decreases the c-MYC level in poorly differentiated prostate cancer cell lines and has a therapeutic potential in castration- and docetaxel-resistant prostate cancer. Nature Publishing Group 2016-12 2016-06-28 /pmc/articles/PMC5133270/ /pubmed/27349498 http://dx.doi.org/10.1038/pcan.2016.21 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Gupta, S Weston, A Bearrs, J Thode, T Neiss, A Soldi, R Sharma, S Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells |
title | Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells |
title_full | Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells |
title_fullStr | Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells |
title_full_unstemmed | Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells |
title_short | Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells |
title_sort | reversible lysine-specific demethylase 1 antagonist hci-2509 inhibits growth and decreases c-myc in castration- and docetaxel-resistant prostate cancer cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133270/ https://www.ncbi.nlm.nih.gov/pubmed/27349498 http://dx.doi.org/10.1038/pcan.2016.21 |
work_keys_str_mv | AT guptas reversiblelysinespecificdemethylase1antagonisthci2509inhibitsgrowthanddecreasescmycincastrationanddocetaxelresistantprostatecancercells AT westona reversiblelysinespecificdemethylase1antagonisthci2509inhibitsgrowthanddecreasescmycincastrationanddocetaxelresistantprostatecancercells AT bearrsj reversiblelysinespecificdemethylase1antagonisthci2509inhibitsgrowthanddecreasescmycincastrationanddocetaxelresistantprostatecancercells AT thodet reversiblelysinespecificdemethylase1antagonisthci2509inhibitsgrowthanddecreasescmycincastrationanddocetaxelresistantprostatecancercells AT neissa reversiblelysinespecificdemethylase1antagonisthci2509inhibitsgrowthanddecreasescmycincastrationanddocetaxelresistantprostatecancercells AT soldir reversiblelysinespecificdemethylase1antagonisthci2509inhibitsgrowthanddecreasescmycincastrationanddocetaxelresistantprostatecancercells AT sharmas reversiblelysinespecificdemethylase1antagonisthci2509inhibitsgrowthanddecreasescmycincastrationanddocetaxelresistantprostatecancercells |