Wang W.-T.Chen Y.-H.Hsu J.-L.Leu W.-J.Yu C.-C.Chan S.-H.Ho Y.-F.LIH-CHING HSUJIH-HWA GUH2021-06-022021-06-022014281298https://www.scopus.com/inward/record.uri?eid=2-s2.0-84891627738&doi=10.1007%2fs00210-013-0912-x&partnerID=40&md5=022b6179be964b5181c1083a88014f28https://scholars.lib.ntu.edu.tw/handle/123456789/564793Although 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 (ΔΨ m) 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. ? 2013 Springer-Verlag Berlin Heidelberg.[SDGs]SDG3beta tubulin; caspase 3; caspase 7; caspase 8; caspase 9; checkpoint kinase 1; checkpoint kinase 2; cytochrome c; diphenhydramine; etoposide; fexofenadine; histone H3; loratadine; protein BAD; protein Bak; protein bcl 2; protein mcl 1; terfenadine; vorinostat; acetylation; amino terminal sequence; antiproliferative activity; apoptosis; article; cancer cell culture; castration resistant prostate cancer; cell proliferation; comet assay; concentration response; conformational transition; controlled study; DNA damage; DNA fragmentation; enzyme activation; enzyme phosphorylation; flow cytometry; human; human cell; in vitro study; male; mitochondrial membrane potential; protein cleavage; real time polymerase chain reaction; upregulation; Western blotting; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; Cell Proliferation; Dose-Response Relationship, Drug; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Myeloid Cell Leukemia Sequence 1 Protein; Prostatic Neoplasms; Receptors, Histamine; Terfenadine; Tumor Cells, Cultured; Up-Regulationjournal article10.1007/s00210-013-0912-x240484392-s2.0-84891627738