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Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells

The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311....

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Autores principales: Niemira, Magdalena, Borowa-Mazgaj, Barbara, Bader, Samuel B., Moszyńska, Adrianna, Ratajewski, Marcin, Karaś, Kaja, Kwaśniewski, Mirosław, Krętowski, Adam, Mazerska, Zofia, Hammond, Ester M., Skwarska, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555468/
https://www.ncbi.nlm.nih.gov/pubmed/32825120
http://dx.doi.org/10.3390/biomedicines8090292
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author Niemira, Magdalena
Borowa-Mazgaj, Barbara
Bader, Samuel B.
Moszyńska, Adrianna
Ratajewski, Marcin
Karaś, Kaja
Kwaśniewski, Mirosław
Krętowski, Adam
Mazerska, Zofia
Hammond, Ester M.
Skwarska, Anna
author_facet Niemira, Magdalena
Borowa-Mazgaj, Barbara
Bader, Samuel B.
Moszyńska, Adrianna
Ratajewski, Marcin
Karaś, Kaja
Kwaśniewski, Mirosław
Krętowski, Adam
Mazerska, Zofia
Hammond, Ester M.
Skwarska, Anna
author_sort Niemira, Magdalena
collection PubMed
description The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (PSA) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa.
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spelling pubmed-75554682020-10-19 Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells Niemira, Magdalena Borowa-Mazgaj, Barbara Bader, Samuel B. Moszyńska, Adrianna Ratajewski, Marcin Karaś, Kaja Kwaśniewski, Mirosław Krętowski, Adam Mazerska, Zofia Hammond, Ester M. Skwarska, Anna Biomedicines Article The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (PSA) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa. MDPI 2020-08-19 /pmc/articles/PMC7555468/ /pubmed/32825120 http://dx.doi.org/10.3390/biomedicines8090292 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Niemira, Magdalena
Borowa-Mazgaj, Barbara
Bader, Samuel B.
Moszyńska, Adrianna
Ratajewski, Marcin
Karaś, Kaja
Kwaśniewski, Mirosław
Krętowski, Adam
Mazerska, Zofia
Hammond, Ester M.
Skwarska, Anna
Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells
title Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells
title_full Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells
title_fullStr Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells
title_full_unstemmed Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells
title_short Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells
title_sort anticancer imidazoacridinone c-1311 is effective in androgen-dependent and androgen-independent prostate cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555468/
https://www.ncbi.nlm.nih.gov/pubmed/32825120
http://dx.doi.org/10.3390/biomedicines8090292
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