Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity
Tóm tắt
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.
Từ khóa
Tài liệu tham khảo
Fassnacht, 2009, Clinical management of adrenocortical carcinoma, Best Pract. Res. Clin. Endocrinol. Metab., 23, 273, 10.1016/j.beem.2008.10.008
Kebebew, 2006, Extent of disease at presentation and outcome for adrenocortical carcinoma: Have we made progress?, World J. Surg., 30, 872, 10.1007/s00268-005-0329-x
Bertherat, 2009, Adrenal tumours and hormone excess, Editorial. Ann. Endocrinol. (Paris), 70, 147, 10.1016/j.ando.2009.02.001
Sinclair, 2020, Surgery for adrenocortical carcinoma: When and how?, Best Pract. Res. Clin. Endocrinol. Metab., 3, 101408, 10.1016/j.beem.2020.101408
Lalli, 2018, The next step: Mechanisms driving adrenocortical carcinoma metastasis, Endocr. Relat. Cancer, 25, R31, 10.1530/ERC-17-0440
Fassnacht, 2012, Combination chemotherapy in advanced adrenocortical carcinoma, N. Engl. J. Med., 366, 2189, 10.1056/NEJMoa1200966
Baudin, 2001, Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p’DDD) levels on the treatment of patients with adrenocortical carcinoma, Cancer, 92, 1385, 10.1002/1097-0142(20010915)92:6<1385::AID-CNCR1461>3.0.CO;2-2
Haak, 1994, Optimal treatment of adrenocortical carcinoma with mitotane: Results in a consecutive series of 96 patients, Br. J. Cancer, 69, 947, 10.1038/bjc.1994.183
Fassnacht, 2011, Adrenocortical carcinoma: A clinician’s update, Nat. Rev. Endocrinol., 7, 323, 10.1038/nrendo.2010.235
Luqmani, 2005, Mechanisms of drug resistance in cancer chemotherapy, Med. Princ. Pract., 14, 35, 10.1159/000086183
Queiroz, 2010, Hedgehog signaling maintains chemoresistance in myeloid leukemic cells, Oncogene, 29, 6314, 10.1038/onc.2010.375
Saze, 2012, Activation of the sonic hedgehog pathway and its prognostic impact in patients with gastric cancer, Dig Surg., 29, 115, 10.1159/000336949
Hasanovic, 2018, Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo, Int. J. Cancer, 143, 199, 10.1002/ijc.31296
Bidet, 2012, The Hedgehog receptor Patched functions in multidrug transport and chemotherapy resistance, Mol. Cancer Res., 10, 1496, 10.1158/1541-7786.MCR-11-0578
Hasanovic, A., and Mus-Veteau, I. (2018). Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency. Cells, 7.
Taylor, 2015, Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach, Drug Resist. Updates, 23, 69, 10.1016/j.drup.2015.08.004
Damaghi, 2013, pH sensing and regulation in cancer, Front. Physiol., 17, 370
Fiorini, 2016, Method to Screen Multidrug Transport Inhibitors Using Yeast Overexpressing a Human MDR Transporter, Methods Mol. Biol., 1432, 303, 10.1007/978-1-4939-3637-3_19
Fiorini, 2015, Natural paniceins from Mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells, Oncotarget, 6, 22282, 10.18632/oncotarget.4162
Signetti, L., Elizarov, N., Simsir, M., Paquet, A., Douguet, D., Labbal, F., Debayle, D., Di Giorgio, A., Biou, V., and Girard, C. (2020). Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma. Cancers (Basel), 12.
Kroiss, 2016, Drug Synergism of Proteasome Inhibitors and Mitotane by Complementary Activation of ER Stress in Adrenocortical Carcinoma Cells, Horm. Cancer, 7, 345, 10.1007/s12672-016-0273-2
Chou, 2006, Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies, Pharmacol. Rev., 58, 621, 10.1124/pr.58.3.10
Choveau, 2009, Transfer of rolf S3-S4 linker to HERG eliminates activation gating but spares inactivation, Biophys. J., 97, 1323, 10.1016/j.bpj.2009.05.060
Trott, 2010, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, J. Comput. Chem., 31, 455, 10.1002/jcc.21334
Pettersen, 2004, UCSF Chimera—A visualization system for exploratory research and analysis, J. Comput. Chem., 25, 1605, 10.1002/jcc.20084
Qian, 2019, Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm, Nat. Commun., 10, 2320, 10.1038/s41467-019-10234-9
Shapovalov, 2011, A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions, Structure, 19, 844, 10.1016/j.str.2011.03.019
Wang, 2006, Automatic atom type and bond type perception in molecular mechanical calculations, J. Mol. Graph. Model., 25, 247, 10.1016/j.jmgm.2005.12.005
Stierand, 2006, Molecular Complexes at a Glance: Automated Generation of two-dimensional Complex Diagrams, Bioinformatics, 22, 1710, 10.1093/bioinformatics/btl150
Bietz, 2017, Proteins Plus: A web portal for structure analysis of macromolecules, Nucleic Acids Res., 45, W337, 10.1093/nar/gkx333
Chang, J.M., Di Tommaso, P., Taly, J.F., and Notredame, C. (2012). Accurate multiple sequence alignment of transmembrane proteins with PSI-Coffee. BMC Bioinform., 13.
Bidet, M., Joubert, O., Lacombe, B., Nehmé, R., Mollat, P., Brétillon, L., Faure, H., Bittman, R., Ruat, M., and Mus-Veteau, I. (2011). The Hedgehog Receptor Patched Contributes to Cholesterol Efflux. PLoS ONE, 6.
Dingerdissen, 2018, BioMuta and BioXpress: Mutation and expression knowledgebases for cancer biomarker discovery, Nucleic Acids Res., 46, D1128, 10.1093/nar/gkx907
Vera, 2017, The combination astemizole-gefitinib as a potential therapy for human lung cancer, Onco Targets Ther., 10, 5795, 10.2147/OTT.S144506
Larrea, 2019, Astemizole, an inhibitor of ether-à-go-go-1 potassium channel, increases the activity of the tyrosine kinase inhibitor gefitinib in breast cancer cells, Rev. Invest. Clin., 71, 186
Du, 2007, A novel structure-based virtual screening model for the hERG channel blockers, Biochem. Biophys. Res. Commun., 355, 889, 10.1016/j.bbrc.2007.02.068
Zhou, 1999, Block of HERG Potassium Channels by the Antihistamine Astemizole and its Metabolites Desmethylastemizole and Norastemizole, J. Cardiovasc. Electrophysiol., 10, 836, 10.1111/j.1540-8167.1999.tb00264.x
Ellegaard, 2016, Repurposing cationic amphiphilic antihistamines for cancer treatment, EBioMedicine, 9, 130, 10.1016/j.ebiom.2016.06.013
Ishikawa, 2000, Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole, Biol. Pharm. Bull., 23, 112, 10.1248/bpb.23.112
Jehle, 2011, Novel roles for hERG K (+) channels in cell proliferation and apoptosis, Cell Death Dis., 2, e193, 10.1038/cddis.2011.77