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....
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
MDPI
2020
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| _version_ | 1797087575364599808 |
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| author | Niemira, M Borowa-Mazgaj, B Bader, SB Moszyńska, A Ratajewski, M Karaś, K Kwaśniewski, M Krętowski, A Mazerska, Z Hammond, EM Skwarska, A |
| author_facet | Niemira, M Borowa-Mazgaj, B Bader, SB Moszyńska, A Ratajewski, M Karaś, K Kwaśniewski, M Krętowski, A Mazerska, Z Hammond, EM Skwarska, A |
| author_sort | Niemira, M |
| collection | OXFORD |
| 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 (<i>PSA</i>) 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. |
| first_indexed | 2024-03-07T02:37:35Z |
| format | Journal article |
| id | oxford-uuid:a9504e6b-d527-4722-a6b6-9ff19dead429 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:37:35Z |
| publishDate | 2020 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oxford-uuid:a9504e6b-d527-4722-a6b6-9ff19dead4292022-03-27T03:07:38ZAnticancer imidazoacridinone C-1311 is effective in androgen-dependent and androgen-independent prostate cancer cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a9504e6b-d527-4722-a6b6-9ff19dead429EnglishSymplectic ElementsMDPI2020Niemira, MBorowa-Mazgaj, BBader, SBMoszyńska, ARatajewski, MKaraś, KKwaśniewski, MKrętowski, AMazerska, ZHammond, EMSkwarska, AThe 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 (<i>PSA</i>) 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. |
| spellingShingle | Niemira, M Borowa-Mazgaj, B Bader, SB Moszyńska, A Ratajewski, M Karaś, K Kwaśniewski, M Krętowski, A Mazerska, Z Hammond, EM Skwarska, A 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 |
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