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

Abstract

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.

Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells

“…We performed a molecular docking on the structure of Ptch1 chain A (pdb 6n7h) [ 16 ]. This structure was chosen because it has the largest central cavity for cholesterol, as explained in previous studies [ 12 , 15 ]. This cavity is localized between the two extracellular domains (ECD) toward the transmembrane domain (TM) ( Figure 3 A) and cholesterol was resolved in this cavity in several of the Ptch1 structures published.…”

“…The second inhibitor, methiothepin, a nonselective 5-HT receptor antagonist, increases the efficacy of dxr against adrenocortical carcinoma cells in vitro and in vivo [ 11 ]. The third inhibitor, astemizole, an anti-histaminergic drug, also increases the efficacy of dxr against adrenocortical carcinoma cells in vitro [ 15 ].…”

The Role of Biomarkers in Adrenocortical Carcinoma: A Review of Current Evidence and Future Perspectives

“…Palbociclib in combination with insulin-like growth factor 1/insulin receptor inhibitor linsitinib shows an additive effect [ 225 ]. Hedgehog Receptor Patched is expressed in ACC and contributes to doxorubicin efflux and treatment resistance [ 226 ]. Utility of the anti-histaminergic drug astemizole, a new inhibitor of Patched drug efflux, was analyzed on ACC cell lines [ 226 ].…”

“…Hedgehog Receptor Patched is expressed in ACC and contributes to doxorubicin efflux and treatment resistance [ 226 ]. Utility of the anti-histaminergic drug astemizole, a new inhibitor of Patched drug efflux, was analyzed on ACC cell lines [ 226 ]. Astemizole at a low concentration sensitizes ACC cells to doxorubicin, magnifying its cytotoxic, proapoptotic and antiproliferative effects [ 226 ].…”

“…Utility of the anti-histaminergic drug astemizole, a new inhibitor of Patched drug efflux, was analyzed on ACC cell lines [ 226 ]. Astemizole at a low concentration sensitizes ACC cells to doxorubicin, magnifying its cytotoxic, proapoptotic and antiproliferative effects [ 226 ]. Withanolides, a group of naturally occurring polyoxygenated steroidal lactones built on an ergostane skeleton, are novel chemotherapeutic agents with potent targeted effects in medullary thyroid cancer and a number of solid malignancies with low toxicity in vivo [ 227 , 228 ].…”