Cargando…

Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy

BACKGROUND: Calcitriol antiproliferative effects include inhibition of the oncogenic ether-à-go-go-1 potassium channel (Eag1) expression, which is necessary for cell cycle progression and tumorigenesis. Astemizole, a new promising antineoplastic drug, targets Eag1 by blocking ion currents. Herein, w...

Descripción completa

Detalles Bibliográficos
Autores principales: García-Quiroz, Janice, García-Becerra, Rocío, Barrera, David, Santos, Nancy, Avila, Euclides, Ordaz-Rosado, David, Rivas-Suárez, Mariana, Halhali, Ali, Rodríguez, Pamela, Gamboa-Domínguez, Armando, Medina-Franco, Heriberto, Camacho, Javier, Larrea, Fernando, Díaz, Lorenza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440370/
https://www.ncbi.nlm.nih.gov/pubmed/22984610
http://dx.doi.org/10.1371/journal.pone.0045063
_version_ 1782243146148610048
author García-Quiroz, Janice
García-Becerra, Rocío
Barrera, David
Santos, Nancy
Avila, Euclides
Ordaz-Rosado, David
Rivas-Suárez, Mariana
Halhali, Ali
Rodríguez, Pamela
Gamboa-Domínguez, Armando
Medina-Franco, Heriberto
Camacho, Javier
Larrea, Fernando
Díaz, Lorenza
author_facet García-Quiroz, Janice
García-Becerra, Rocío
Barrera, David
Santos, Nancy
Avila, Euclides
Ordaz-Rosado, David
Rivas-Suárez, Mariana
Halhali, Ali
Rodríguez, Pamela
Gamboa-Domínguez, Armando
Medina-Franco, Heriberto
Camacho, Javier
Larrea, Fernando
Díaz, Lorenza
author_sort García-Quiroz, Janice
collection PubMed
description BACKGROUND: Calcitriol antiproliferative effects include inhibition of the oncogenic ether-à-go-go-1 potassium channel (Eag1) expression, which is necessary for cell cycle progression and tumorigenesis. Astemizole, a new promising antineoplastic drug, targets Eag1 by blocking ion currents. Herein, we characterized the interaction between calcitriol and astemizole as well as their conjoint antiproliferative action in SUM-229PE, T-47D and primary tumor-derived breast cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: Molecular markers were studied by immunocytochemistry, Western blot and real time PCR. Inhibitory concentrations were determined by dose-response curves and metabolic activity assays. At clinically achievable drug concentrations, synergistic antiproliferative interaction was observed between calcitriol and astemizole, as calculated by combination index analysis (CI <1). Astemizole significantly enhanced calcitriol’s growth-inhibitory effects (3–11 folds, P<0.01). Mean IC(20) values were 1.82±2.41 nM and 1.62±0.75 µM; for calcitriol (in estrogen receptor negative cells) and astemizole, respectively. Real time PCR showed that both drugs alone downregulated, while simultaneous treatment further reduced Ki-67 and Eag1 gene expression (P<0.05). Astemizole inhibited basal and calcitriol-induced CYP24A1 and CYP3A4 mRNA expression (cytochromes involved in calcitriol and astemizole degradation) in breast and hepatoma cancer cells, respectively, while upregulated vitamin D receptor (VDR) expression. CONCLUSIONS/SIGNIFICANCE: Astemizole synergized calcitriol antiproliferative effects by downregulating CYP24A1, upregulating VDR and targeting Eag1. This study provides insight into the molecular mechanisms involved in astemizole-calcitriol combined antineoplastic effect, offering scientific support to test both compounds in combination in further preclinical and clinical studies of neoplasms expressing VDR and Eag1. VDR-negative tumors might also be sensitized to calcitriol antineoplastic effects by the use of astemizole. Herein we suggest a novel combined adjuvant therapy for the management of VDR/Eag1-expressing breast cancer tumors. Since astemizole improves calcitriol bioavailability and activity, decreased calcitriol dosing is advised for conjoint administration.
format Online
Article
Text
id pubmed-3440370
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-34403702012-09-14 Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy García-Quiroz, Janice García-Becerra, Rocío Barrera, David Santos, Nancy Avila, Euclides Ordaz-Rosado, David Rivas-Suárez, Mariana Halhali, Ali Rodríguez, Pamela Gamboa-Domínguez, Armando Medina-Franco, Heriberto Camacho, Javier Larrea, Fernando Díaz, Lorenza PLoS One Research Article BACKGROUND: Calcitriol antiproliferative effects include inhibition of the oncogenic ether-à-go-go-1 potassium channel (Eag1) expression, which is necessary for cell cycle progression and tumorigenesis. Astemizole, a new promising antineoplastic drug, targets Eag1 by blocking ion currents. Herein, we characterized the interaction between calcitriol and astemizole as well as their conjoint antiproliferative action in SUM-229PE, T-47D and primary tumor-derived breast cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: Molecular markers were studied by immunocytochemistry, Western blot and real time PCR. Inhibitory concentrations were determined by dose-response curves and metabolic activity assays. At clinically achievable drug concentrations, synergistic antiproliferative interaction was observed between calcitriol and astemizole, as calculated by combination index analysis (CI <1). Astemizole significantly enhanced calcitriol’s growth-inhibitory effects (3–11 folds, P<0.01). Mean IC(20) values were 1.82±2.41 nM and 1.62±0.75 µM; for calcitriol (in estrogen receptor negative cells) and astemizole, respectively. Real time PCR showed that both drugs alone downregulated, while simultaneous treatment further reduced Ki-67 and Eag1 gene expression (P<0.05). Astemizole inhibited basal and calcitriol-induced CYP24A1 and CYP3A4 mRNA expression (cytochromes involved in calcitriol and astemizole degradation) in breast and hepatoma cancer cells, respectively, while upregulated vitamin D receptor (VDR) expression. CONCLUSIONS/SIGNIFICANCE: Astemizole synergized calcitriol antiproliferative effects by downregulating CYP24A1, upregulating VDR and targeting Eag1. This study provides insight into the molecular mechanisms involved in astemizole-calcitriol combined antineoplastic effect, offering scientific support to test both compounds in combination in further preclinical and clinical studies of neoplasms expressing VDR and Eag1. VDR-negative tumors might also be sensitized to calcitriol antineoplastic effects by the use of astemizole. Herein we suggest a novel combined adjuvant therapy for the management of VDR/Eag1-expressing breast cancer tumors. Since astemizole improves calcitriol bioavailability and activity, decreased calcitriol dosing is advised for conjoint administration. Public Library of Science 2012-09-12 /pmc/articles/PMC3440370/ /pubmed/22984610 http://dx.doi.org/10.1371/journal.pone.0045063 Text en © 2012 García-Quiroz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
García-Quiroz, Janice
García-Becerra, Rocío
Barrera, David
Santos, Nancy
Avila, Euclides
Ordaz-Rosado, David
Rivas-Suárez, Mariana
Halhali, Ali
Rodríguez, Pamela
Gamboa-Domínguez, Armando
Medina-Franco, Heriberto
Camacho, Javier
Larrea, Fernando
Díaz, Lorenza
Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy
title Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy
title_full Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy
title_fullStr Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy
title_full_unstemmed Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy
title_short Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy
title_sort astemizole synergizes calcitriol antiproliferative activity by inhibiting cyp24a1 and upregulating vdr: a novel approach for breast cancer therapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440370/
https://www.ncbi.nlm.nih.gov/pubmed/22984610
http://dx.doi.org/10.1371/journal.pone.0045063
work_keys_str_mv AT garciaquirozjanice astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT garciabecerrarocio astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT barreradavid astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT santosnancy astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT avilaeuclides astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT ordazrosadodavid astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT rivassuarezmariana astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT halhaliali astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT rodriguezpamela astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT gamboadominguezarmando astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT medinafrancoheriberto astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT camachojavier astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT larreafernando astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy
AT diazlorenza astemizolesynergizescalcitriolantiproliferativeactivitybyinhibitingcyp24a1andupregulatingvdranovelapproachforbreastcancertherapy