title: Terfenadine induces anti-proliferative and apoptotic activities in human hormone-refractory prostate cancer through histamine receptor-independent Mcl-1 cleavage and Bak up-regulation.
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.
authors.affiliation: School of Pharmacy, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Wang
authors.forename: Yen-Hui
authors.initials: YH
authors.lastname: Chen
authors.forename: Jui-Ling
authors.initials: JL
authors.lastname: Hsu
authors.forename: Wohn-Jenn
authors.initials: WJ
authors.lastname: Leu
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Yu
authors.forename: She-Hung
authors.initials: SH
authors.lastname: Chan
authors.forename: Yunn-Fang
authors.initials: YF
authors.lastname: Ho
authors.forename: Lih-Ching
authors.initials: LC
authors.lastname: Hsu
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology*; D006801:Humans; D008297:Male; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011968:Receptors, Histamine / Q000502:physiology; D016593:Terfenadine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000819:agonists / Q000096:biosynthesis*
chemical_list: C494772:BAK1 protein, human; D039563:Histamine H1 Antagonists, Non-Sedating; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011968:Receptors, Histamine; D050998:bcl-2 Homologous Antagonist-Killer Protein; D016593:Terfenadine
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