title: HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
abstract: Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.
authors: Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Ingo
authors: I
authors: Staudacher
authors: Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Julian
authors: J
authors: Jehle
authors: Department of Neonatology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Kathrin
authors: K
authors: Staudacher
authors: Department of Neurooncology, University Hospital Heidelberg, Heidelberg, Germany ; German Cancer Consortium Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany.
authors: Hans-Werner
authors: HW
authors: Pledl
authors: Department of Neurooncology, University Hospital Heidelberg, Heidelberg, Germany ; German Cancer Consortium Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany.
authors: Dieter
authors: D
authors: Lemke
authors: Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Patrick A
authors: PA
authors: Schweizer
authors: Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Rüdiger
authors: R
authors: Becker
authors: Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Hugo A
authors: HA
authors: Katus
authors: Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Dierk
authors: D
authors: Thomas
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D053453:Caspase 9 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology; D017292:Doxazosin / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D004789:Enzyme Activation / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D034741:RNA, Small Interfering; D053453:Caspase 9; D017292:Doxazosin; D003891:Desipramine