探討α1-交感神經受體阻斷劑在人類前列腺癌細胞的抗癌作用機轉 -體內及體外試驗

Investigation of Anticancer Mechanism of alpha1-Adrenoceptor antagonist in Human Prostate Cancer -In vitro and in vivo Studies

林思嘉(Ssu-Chia Lin)

指導教授 ： 顧記華

共同指導教授 ： 闕士傑(shih chieh chueh)

國立臺灣大學/醫學院/藥學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.02362

摘要

無資料

關鍵字

交感神經受體阻斷劑 ； 細胞凋亡 ； 前列腺癌 ； 基因體受損 ； 細胞週期停滯

並列摘要

Quinazoline-based α1-adrenoceptor antagonists, such as doxazosin and terazosin, have been demonstrated to display anticancer effect in prostate cancer cell lines via a α1-adrenoceptor-independent pathway. In this study, the data showed that several clinically used α1-adrenoceptor antagonists exhibited varied efficacies on the inhibition of PC-3 proliferation by sulforhodamine B (SRB) assay with rank order of prazosin (IC50 = 11.1 μM) > doxazosin (20.6 μM) > phentolamine (58.3 μM) > terazosin (62.6 μM) > tamsulosin (> 100 μM). Similar results were also obtained in other two human prostate cancer cell lines including DU145 and LNCaP. The SRB assay showed that prazosin could display additive effect in combination with doxorubicin, but not camptothecin, mitoxantrone, etoposide, taxol or vincristine. Since prazosin showed the most effective effect, the anticancer mechanism was investigated in this study. By FACScan flow cytometric analysis, the data showed that prazosin induced G2/M arrest and a subsequent increase of hypodiploid phase (apoptosis) of the cell cycle in a time- and concentration-dependent manner. However, the sustained elevation of cyclin A1 and the absence of MPM2 expression suggested that prazosin induced G2- other than mitotic arrest in PC-3 cells. Moreover, prazosin induced an increase of phosphorylation at Ser216 of Cdc25C and a decrease of dephosphorylation at Tyr15 of Cdk1 concomitant with the cytoplasmic sequestration of Cdc25C, suggesting that prazosin induced the inactivation of Cdk1 activity. By comet assay, a short term (one hour) treatment of prazosin was able to cause DNA damage. It could also induce the cleavage of anti-apoptosis members of Bcl-2 family, such as Bcl-2 and Mcl-1, and the activation of caspase cascades. In animal study, the orally administered prazosin (3 and 10 mg/kg) could partly inhibit the PC-3 tumor growth of 50.4 and 64.7%, respectively. Taken together, it is suggested that prazosin is an effective anti-tumor agent both in in vitro and in vivo tests. It induces DNA damage and G2 arrest of the cell cycle and the subsequent apoptosis through an inactivation of Cdk1 activity, the cleavage of anti-apoptosis members of Bcl-2 family and the activation of caspase cascades.

並列關鍵字

prazosin ； apoptosis ； prostate cancer ； DNA damage ； G2 arrest

參考文獻

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