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 tumorsReportar como inadecuado




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 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Cancer

, 14:745

Experimental therapeutics and drug development

Abstract

BackgroundThe 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.

MethodsIn 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.

ResultsCompared 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.

ConclusionsThe 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.

KeywordsVitamin D Breast cancer Vitamin D receptor Targeted therapy Ki-67 EAG1 AbbreviationsEAG1Ether-à-go-go-1 potassium channel

VDRVitamin D receptor.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-745 contains supplementary material, which is available to authorized users.

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Autor: Janice García-Quiroz - Rocío García-Becerra - Nancy Santos-Martínez - David Barrera - David Ordaz-Rosado - Euclides Avil

Fuente: https://link.springer.com/







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