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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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/8/251 |
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| author | Anida Hasanovic Méliné Simsir Frank S. Choveau Enzo Lalli Isabelle Mus-Veteau |
| author_facet | Anida Hasanovic Méliné Simsir Frank S. Choveau Enzo Lalli Isabelle Mus-Veteau |
| author_sort | Anida Hasanovic |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T18:08:18Z |
| format | Article |
| id | doaj.art-95c3ebc4b32a43f4890c866c3f3575ac |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T18:08:18Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-95c3ebc4b32a43f4890c866c3f3575ac2023-11-20T08:18:03ZengMDPI AGBiomedicines2227-90592020-07-018825110.3390/biomedicines8080251Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux ActivityAnida Hasanovic0Méliné Simsir1Frank S. Choveau2Enzo Lalli3Isabelle Mus-Veteau4Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, FranceUniversité Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, FranceUniversité Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, FranceUniversité Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, FranceUniversité Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, FranceAdrenocortical 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.https://www.mdpi.com/2227-9059/8/8/251adrenocortical carcinomaPatcheddrug efflux pumpchemotherapy resistancesmall lead moleculerepositioning |
| spellingShingle | Anida Hasanovic Méliné Simsir Frank S. Choveau Enzo Lalli Isabelle Mus-Veteau Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity Biomedicines adrenocortical carcinoma Patched drug efflux pump chemotherapy resistance small lead molecule repositioning |
| title | Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity |
| title_full | Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity |
| title_fullStr | Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity |
| title_full_unstemmed | Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity |
| title_short | Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity |
| title_sort | astemizole sensitizes adrenocortical carcinoma cells to doxorubicin by inhibiting patched drug efflux activity |
| topic | adrenocortical carcinoma Patched drug efflux pump chemotherapy resistance small lead molecule repositioning |
| url | https://www.mdpi.com/2227-9059/8/8/251 |
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