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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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Abstract

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.

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Acknowledgments

We acknowledge the support provided by the National Science Council of the Republic of China (NSC 101-2320-B-002-018-MY3 and NSC 100-2320-B-002-006-MY3).

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Authors and Affiliations

  1. School of Pharmacy, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan

    Wei-Ting Wang, Jui-Ling Hsu, Wohn-Jenn Leu, Chia-Chun Yu, She-Hung Chan, Lih-Ching Hsu & Jih-Hwa Guh

  2. Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei, 100, Taiwan

    Yen-Hui Chen & Yunn-Fang Ho

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  1. Wei-Ting Wang
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Correspondence to Jih-Hwa Guh.

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Wei-Ting Wang and Yen-Hui Chen contributed equally to this work.

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Wang, WT., Chen, YH., Hsu, JL. et al. Terfenadine induces anti-proliferative and apoptotic activities in human hormone-refractory prostate cancer through histamine receptor-independent Mcl-1 cleavage and Bak up-regulation. Naunyn-Schmiedeberg's Arch Pharmacol 387, 33–45 (2014). https://doi.org/10.1007/s00210-013-0912-x

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