Terfenadine induces anti-proliferative and apoptotic activities in human hormone-refractory prostate cancer through histamine receptor-independent Mcl-1 cleavage and Bak up-regulation

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• 作者：Wei-Ting Wang (1)
  Yen-Hui Chen (2)
  Jui-Ling Hsu (1)
  Wohn-Jenn Leu (1)
  Chia-Chun Yu (1)
  She-Hung Chan (1)
  Yunn-Fang Ho (2)
  Lih-Ching Hsu (1)
  Jih-Hwa Guh (1)
  
• 关键词：Terfenadine ; H1 ; histamine receptor antagonist ; Mcl ; 1 cleavage ; Bak up ; regulation ; Hormone ; refractory prostate cancer
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2014
• 出版时间：January 2014
• 年：2014
• 卷：387
• 期：1
• 页码：33-45
• 全文大小：
• 作者单位：Wei-Ting Wang (1)
  Yen-Hui Chen (2)
  Jui-Ling Hsu (1)
  Wohn-Jenn Leu (1)
  Chia-Chun Yu (1)
  She-Hung Chan (1)
  Yunn-Fang Ho (2)
  Lih-Ching Hsu (1)
  Jih-Hwa Guh (1)
  
  1. School of Pharmacy, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan
  2. Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei, 100, Taiwan
  
• ISSN：1432-1912

文摘

Although the results of several studies have underscored the regulatory effect of H1-histamine receptors in cell proliferation of some cancer cell types, its effect in prostate cancers remains unclear. We have therefore studied the effect of terfenadine (an H1-histamine receptor antagonist) in prostate cancer cell lines. Our data demonstrate that terfenadine was effective against PC-3 and DU-145 cells (two prostate cancer cell lines). In contrast, based on the sulforhodamine B assay, loratadine had less potency while fexofenadine and diphenhydramine had little effect. Terfenadine induced the cleavage of Mcl-1 cleavage into a pro-apoptotic 28-kDa fragment and up-regulation of Bak, resulting in the loss of mitochondrial membrane potential (ΔΨm) and the release of cytochrome c and apoptosis-inducing factor into the cytosol. The activation of caspase cascades was detected to be linked to terfenadine action. Bak up-regulation was also examined at both the transcriptional and translational levels, and Bak activation was validated based on conformational change to expose the N terminus. Terfenadine also induced an indirect—but not direct—DNA damage response through the cleavage and activation of caspase-2, phosphorylation and activation of Chk1 and Chk2 kinases, phosphorylation of RPA32 and acetylation of Histone H3; these processes were highly correlated to severe mitochondrial dysfunction and the activation of caspase cascades. In conclusion, terfenadine induced apoptotic signaling cascades against HRPCs in a sequential manner. The exposure of cells to terfenadine caused the up-regulation and activation of Bak and the cleavage of Mcl-1, leading to the loss of ΔΨm and activation of caspase cascades which further resulted in DNA damage response and cell apoptosis.