Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells
Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/2/103 |
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| author | Zohaib Rana Joel D. A. Tyndall Muhammad Hanif Christian G. Hartinger Rhonda J. Rosengren |
| author_facet | Zohaib Rana Joel D. A. Tyndall Muhammad Hanif Christian G. Hartinger Rhonda J. Rosengren |
| author_sort | Zohaib Rana |
| collection | DOAJ |
| description | Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G<sub>0</sub>/G<sub>1</sub> arrest in AR-null cells, whereas Jazz167 leads to a G<sub>0</sub>/G<sub>1</sub> arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells. |
| first_indexed | 2024-03-09T03:20:16Z |
| format | Article |
| id | doaj.art-551f0a6073ae4aec8deed1164883d3a7 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T03:20:16Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-551f0a6073ae4aec8deed1164883d3a72023-12-03T15:10:17ZengMDPI AGPharmaceuticals1424-82472021-01-0114210310.3390/ph14020103Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer CellsZohaib Rana0Joel D. A. Tyndall1Muhammad Hanif2Christian G. Hartinger3Rhonda J. Rosengren4Department of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New ZealandSchool of Pharmacy, University of Otago, Dunedin 9016, New ZealandSchool of Chemical Sciences, University of Auckland, Auckland 1142, New ZealandSchool of Chemical Sciences, University of Auckland, Auckland 1142, New ZealandDepartment of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New ZealandAndrogen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G<sub>0</sub>/G<sub>1</sub> arrest in AR-null cells, whereas Jazz167 leads to a G<sub>0</sub>/G<sub>1</sub> arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.https://www.mdpi.com/1424-8247/14/2/103HDAC inhibitorscancer chemotherapyprostate cancerpyridinecarbothioamidemetallodrugsanticancer agents |
| spellingShingle | Zohaib Rana Joel D. A. Tyndall Muhammad Hanif Christian G. Hartinger Rhonda J. Rosengren Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells Pharmaceuticals HDAC inhibitors cancer chemotherapy prostate cancer pyridinecarbothioamide metallodrugs anticancer agents |
| title | Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells |
| title_full | Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells |
| title_fullStr | Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells |
| title_full_unstemmed | Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells |
| title_short | Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells |
| title_sort | cytostatic action of novel histone deacetylase inhibitors in androgen receptor null prostate cancer cells |
| topic | HDAC inhibitors cancer chemotherapy prostate cancer pyridinecarbothioamide metallodrugs anticancer agents |
| url | https://www.mdpi.com/1424-8247/14/2/103 |
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