title: In vivo dual targeting of the oncogenic Ether-à-go-go-1 potassium channel by calcitriol and astemizole results in enhanced antineoplastic effects in breast tumors.
abstract: BACKGROUND
  The oncogenic ether-à-go-go-1 potassium channel (EAG1) activity and expression are necessary for cell cycle progression and tumorigenesis. The active vitamin D metabolite, calcitriol, and astemizole, a promising antineoplastic drug, target EAG1 by inhibiting its expression and blocking ion currents, respectively. We have previously shown a synergistic antiproliferative effect of calcitriol and astemizole in breast cancer cells in vitro, but the effect of this dual therapy in vivo has not been studied.
  
  
  METHODS
  In the present study, we explored the combined antineoplastic effect of both drugs in vivo using mice xenografted with the human breast cancer cell line T-47D and a primary breast cancer-derived cell culture (MBCDF). Tumor-bearing athymic female mice were treated with oral astemizole (50 mg/kg/day) and/or intraperitoneal injections of calcitriol (0.03 μg/g body weight twice a week) during 3 weeks. Tumor sizes were measured thrice weekly. For mechanistic insights, we studied EAG1 expression by qPCR and Western blot. The expression of Ki-67 and the relative tumor volume were used as indicators of therapeutic efficacy.
  
  
  RESULTS
  Compared to untreated controls, astemizole and calcitriol significantly reduced, while the coadministration of both drugs further suppressed, tumor growth (P < 0.05). In addition, the combined therapy significantly downregulated tumoral EAG1 and Ki-67 expression.
  
  
  CONCLUSIONS
  The concomitant administration of calcitriol and astemizole inhibited tumor growth more efficiently than each drug alone, which may be explained by the blocking of EAG1. These results provide the bases for further studies aimed at testing EAG1-dual targeting in breast cancer tumors expressing both EAG1 and the vitamin D receptor.
authors.forename: Janice
authors.initials: J
authors.lastname: García-Quiroz
authors.forename: Rocío
authors.initials: R
authors.lastname: García-Becerra
authors.forename: Nancy
authors.initials: N
authors.lastname: Santos-Martínez
authors.forename: David
authors.initials: D
authors.lastname: Barrera
authors.forename: David
authors.initials: D
authors.lastname: Ordaz-Rosado
authors.forename: Euclides
authors.initials: E
authors.lastname: Avila
authors.forename: Ali
authors.initials: A
authors.lastname: Halhali
authors.forename: Octavio
authors.initials: O
authors.lastname: Villanueva
authors.forename: Maŕa J
authors.initials: MJ
authors.lastname: Ibarra-Sánchez
authors.forename: José
authors.initials: J
authors.lastname: Esparza-López
authors.forename: Armando
authors.initials: A
authors.lastname: Gamboa-Domínguez
authors.forename: Javier
authors.initials: J
authors.lastname: Camacho
authors.forename: Fernando
authors.initials: F
authors.lastname: Larrea
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No, 15, Tlalpan, México, DF 14000, México. lorenzadiaz@gmail.com.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Díaz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D016589:Astemizole / Q000008:administration & dosage* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D002117:Calcitriol / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004357:Drug Synergism; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation
chemical_list: D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; C496885:Kcnh1 protein, mouse; D016589:Astemizole; D002117:Calcitriol