Abstract P4-06-19: Astemizole and calcitriol: A novel targeted therapeutic strategy for breast cancer

Abstract

Abstract Calcitriol antiproliferative effects include inhibition of the oncogenic ether-à-go-go-1 potassium channel (Eag1), which expression and activity are necessary for cell cycle progression and tumorigenesis. Astemizole, a new promising antineoplastic drug, targets Eag1 by blocking ion currents. In vitro, we showed that astemizole synergized calcitriol antiproliferative effects by downregulating CYP24A1, the enzyme that degrades calcitriol, and upregulating the vitamin D receptor (VDR), which mediates calcitriol actions. In this study we investigated the antineoplastic effect of astemizole and calcitriol in a murine model xenografted with T-47D and invasive ductal carcinoma-derived breast cancer cells (IDC). Tumor-bearing nude mice were treated with oral astemizole (50 mg/kg/day) and/or i.p. calcitriol (30 μg/kg/twice a week) during 3 weeks. Astemizole and calcitriol significantly inhibited, while the coadministration of both drugs further reduced, tumor growth compared to untreated controls. These results were supported by immunohistochemistry studies of Ki-67, a proliferation marker, which revealed less staining in tumors from mice with the co-treatment compared to controls and calcitriol or astemizole alone. In a similar manner as reported in vitro, we observed that the concomitant administration of astemizole and calcitriol upregulated VDR tumor expression (P < 0.05). Conclusion: Coadministration of calcitriol and astemizole increased the antineoplastic effects of both drugs. Our results indicate that astemizole may improve calcitriol bioactivity by upregulating tumoral VDR. In addition, the findings in this study suggest that VDR-negative tumors could be sensitized to calcitriol antineoplastic effects by concomitant administration with astemizole, which would also allow for less calcitriol dosing without sacrificing overall therapeutic efficacy. Herein we suggest a novel combined adjuvant therapy for the management of breast cancer tumors. These results provide scientific bases for further studies designed to test both compounds simultaneously in patients bearing solid or metastatic tumors. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-19.