Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity

Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatmen...

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Bibliographic Details
Published in:Biomedicines 2020-07, Vol.8 (8), p.251
Main Authors: Hasanovic, Anida, Simsir, Méliné, Choveau, Frank S., Lalli, Enzo, Mus-Veteau, Isabelle
Format: Article
Language:English
Subjects:
adrenocortical carcinoma
Apoptosis
Cancer
Cancer therapies
Chemotherapy
chemotherapy resistance
Cisplatin
Cloning
Cytotoxicity
Doxorubicin
Drug dosages
drug efflux pump
Etoposide
Glucose
Life Sciences
Medical prognosis
Metastases
Metastasis
Patched
Pharmaceutical sciences
Protonmotive force
repositioning
small lead molecule
Surgery
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Summary:Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatment resistance. Here, we report the identification of a new inhibitor of Patched drug efflux, the anti-histaminergic drug astemizole. We show that astemizole enhances the cytotoxic, proapoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells at concentrations of astemizole or doxorubicin that are not effective by themselves. Our results suggest that a low concentration of astemizole sensitizes ACC cells to doxorubicin, which is a component of the standard treatment for ACC composed of etoposide, doxorubicin, cisplatin and mitotane (EDPM). Patched uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that the use of astemizole or a derivative in combination with EDPM could be a promising therapeutic option for ACC by increasing the treatment effectiveness at lower doses of EDPM, which would reduce the severe side effects of this regimen.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines8080251