Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle
Quinazoline-based α1,-adrenoceptor antagonists, in particular doxazosin, terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to t...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2007-10-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558607800637 |
| _version_ | 1819057510552698880 |
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| author | Ssu-Chia Lin Shih-Chieh Chueht Che-Jen Hsiao Tsia-Kun Li Tzu-Hsuan Chen Cho-Hwa Liao Ping-Chiang Lyu Jih-Hwa Guh |
| author_facet | Ssu-Chia Lin Shih-Chieh Chueht Che-Jen Hsiao Tsia-Kun Li Tzu-Hsuan Chen Cho-Hwa Liao Ping-Chiang Lyu Jih-Hwa Guh |
| author_sort | Ssu-Chia Lin |
| collection | DOAJ |
| description | Quinazoline-based α1,-adrenoceptor antagonists, in particular doxazosin, terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other α1-blockers, including doxazosin, terazosin, tamsulosin, phentolamine. Prazosin induced G2 checkpoint arrest, subsequent apoptosis in prostate cancer PC-3, DU-145, LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA str, breaks, ATM/ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr15. The data, together with sustained elevated cyclin A levels (other than cyclin B1 levels), suggested that Cdki activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated, caspaseexecuted apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdki inactivation, G2 checkpoint arrest. Subsequently, mitochondriamediated caspase cascades are triggered to induce apoptosis in PC-3 cells. |
| first_indexed | 2024-12-21T13:40:27Z |
| format | Article |
| id | doaj.art-9c469a29db2940449599a3e83b9f2422 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-21T13:40:27Z |
| publishDate | 2007-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-9c469a29db2940449599a3e83b9f24222022-12-21T19:02:02ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022007-10-0191083083910.1593/neo.07475Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell CycleSsu-Chia Lin0Shih-Chieh Chueht1Che-Jen Hsiao2Tsia-Kun Li3Tzu-Hsuan Chen4Cho-Hwa Liao5Ping-Chiang Lyu6Jih-Hwa Guh7School of Pharmacy, National Taiwan University, Taipei, TaiwanDepartment of Urology, National Taiwan University Hospital, Taipei, TaiwanDepartment of Life Sciences, Institute of Bioinformatics, Structural Biology, National Tsing Hua University, Hsinchu, TaiwanDepartment of Microbiology, College of Medicine, National Taiwan University, Taipei, TaiwanSchool of Pharmacy, National Taiwan University, Taipei, TaiwanSchool of Pharmacy, National Taiwan University, Taipei, TaiwanDepartment of Life Sciences, Institute of Bioinformatics, Structural Biology, National Tsing Hua University, Hsinchu, TaiwanSchool of Pharmacy, National Taiwan University, Taipei, TaiwanQuinazoline-based α1,-adrenoceptor antagonists, in particular doxazosin, terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other α1-blockers, including doxazosin, terazosin, tamsulosin, phentolamine. Prazosin induced G2 checkpoint arrest, subsequent apoptosis in prostate cancer PC-3, DU-145, LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA str, breaks, ATM/ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr15. The data, together with sustained elevated cyclin A levels (other than cyclin B1 levels), suggested that Cdki activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated, caspaseexecuted apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdki inactivation, G2 checkpoint arrest. Subsequently, mitochondriamediated caspase cascades are triggered to induce apoptosis in PC-3 cells.http://www.sciencedirect.com/science/article/pii/S1476558607800637PrazosinDNA damagecell cycleCdc25cmitochondriainvolved apoptosis |
| spellingShingle | Ssu-Chia Lin Shih-Chieh Chueht Che-Jen Hsiao Tsia-Kun Li Tzu-Hsuan Chen Cho-Hwa Liao Ping-Chiang Lyu Jih-Hwa Guh Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle Neoplasia: An International Journal for Oncology Research Prazosin DNA damage cell cycle Cdc25c mitochondriainvolved apoptosis |
| title | Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle |
| title_full | Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle |
| title_fullStr | Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle |
| title_full_unstemmed | Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle |
| title_short | Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle |
| title_sort | prazosin displays anticancer activity against human prostate cancers targeting dna cell cycle |
| topic | Prazosin DNA damage cell cycle Cdc25c mitochondriainvolved apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S1476558607800637 |
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