title: Astemizole-based anticancer therapy for hepatocellular carcinoma (HCC), and Eag1 channels as potential early-stage markers of HCC.
abstract: Hepatocellular carcinoma (HCC) has very poor prognosis. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including the Eag1 (ether à-go-go-1) potassium channel that is overexpressed in human HCC. Eag1 channels are regulated by cancer etiological factors and have been proposed as early tumor markers. Here, we found that HepG2 and HuH-7 HCC cells displayed Eag1 messenger RNA (mRNA) and protein expression, determined by real-time RT-PCR and immunochemistry, respectively. Astemizole inhibited human HCC cell proliferation (assessed by metabolic activity assay) and induced apoptosis (studied with flow cytometry) in both cell lines. The subcellular Eag1 protein localization was modified by astemizole in the HepG2 cells. The treatment with astemizole prevented diethylnitrosamine (DEN)-induced rat HCC development in vivo (followed by studying γ-glutamyl transpeptidase (GGT) activity). The Eag1 mRNA and protein levels were increased in most DEN-treated groups but decreased after astemizole treatment. GGT activity was decreased by astemizole. The Eag1 protein was detected in cirrhotic and dysplastic rat livers. Astemizole might have clinical utility for HCC prevention and treatment, and Eag1 channels may be potential early HCC biomarkers. These data provide significant basis to include astemizole in HCC clinical trials.
authors.affiliation: Department of Pharmacology, Centro de Investigación y de Estudios Avanzados del I.P.N., Avenida Instituto Politécnico Nacional 2508, Mexico City, 07360, Mexico.
authors.forename: María
authors.initials: M
authors.lastname: de Guadalupe Chávez-López
authors.forename: Julio Isael
authors.initials: JI
authors.lastname: Pérez-Carreón
authors.forename: Violeta
authors.initials: V
authors.lastname: Zuñiga-García
authors.forename: José
authors.initials: J
authors.lastname: Díaz-Chávez
authors.forename: Luis A
authors.initials: LA
authors.lastname: Herrera
authors.forename: Claudia Haydee
authors.initials: CH
authors.lastname: Caro-Sánchez
authors.forename: Isabel
authors.initials: I
authors.lastname: Acuña-Macías
authors.forename: Patricio
authors.initials: P
authors.lastname: Gariglio
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hernández-Gallegos
authors.forename: Andrea Jazmín
authors.initials: AJ
authors.lastname: Chiliquinga
authors.forename: Javier
authors.initials: J
authors.lastname: Camacho
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016589:Astemizole / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000008:administration & dosage; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D004052:Diethylnitrosamine; D016589:Astemizole; D005723:gamma-Glutamyltransferase; C554782:gamma-glutamyltransferase, human