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The Hedgehog receptor Patched regulates Hedgehog signaling by transporting cholesterol. Hedgehog signaling is aberrantly activated and Patched is overexpressed in many recurrent and metastatic cancers. We showed that Patched pumps chemotherapeutic agents such as doxorubicin out of cancer cells using the proton motive force and contributes to chemotherapy resistance of several cancer cell types, and that cells overexpressing Patched at their plasma membrane have persistent (or cancer stem cell) properties.
We identified small molecules which inhibit the doxorubicin efflux activity of Patched and enhance its cytotoxicity on adrenocortical carcinoma and melanoma cells that endogenously overexpress Patched, and thereby mitigates the resistance of these cancer cells to doxorubicin. We also showed that these Patched drug efflux inhibitors enhance the efficacy of kinase inhibitors such as vemurafenib against melanoma cells resistant to the treatment in cellulo and in vivo on xenografts in mice.
Our data suggest that the use of inhibitors of Patched drug efflux in combination with chemotherapy could be a promising therapeutic option to improve chemotherapy efficiency against cancer cells expressing Patched.
- Feliz Morel, Á.J.; Hasanovic, A.; Morin, A.; Prunier, C.; Magnone, V.; Lebrigand, K.; Aouad, A.; Cogoluegnes, S.; Favier, J.; Pasquier, C.; Mus-Veteau, I. Persistent Properties of a Subpopulation of Cancer Cells Overexpressing the Hedgehog Receptor Patched. Pharmaceutics 2022, 14, 988. https://doi.org/10.3390/pharmaceutics14050988
- Kovachka S, Malloci G, Simsir M, Ruggerone P, Azoulay S, Mus-Veteau I. Inhibition of the drug efflux activity of Ptch1 as a promising strategy to overcome chemotherapy resistance in cancer cells. Eur J Med Chem. 2022 Jun 5;236:114306. doi: 10.1016/j.ejmech.2022.114306. Epub 2022 Mar 29. PMID: 35421658.
- Durand N, Simsir M, Signetti L, Labbal F, Ballotti R, Mus-Veteau I. Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells. Molecules. 2021 Mar 26;26(7):1867.
- Kovachka, G. Malloci, A.V. Vargiu, S. Azoulay, I. Mus-Veteau, P. Ruggerone, Molecular insights into the Patched1 drug efflux inhibitory activity of panicein A hydroquinone: a computational study, Phys. Chem. Chem. Phys. 23 (2021) 8013–8022.
- Simsir M and Mus-Veteau I, RND family efflux pumps: from antibioresistance to chemotherapy resistanceSwed J BioSci Res 2020; 1(1): 51 - 61. Review.DOI: https://doi.org/10.51136/sjbsr.2020.51.61
- Simsir M, Broutin I, Mus-Veteau I, Cazals F. Studying dynamics without explicit dynamics: A structure-based study of the export mechanism by AcrB. Proteins. 2020 Sep 22. doi: 10.1002/prot.26012. Epub ahead of print. PMID: 32960482.
- Hasanovic A, Simsir M, Choveau FS, Lalli E, Mus-Veteau I. Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity. Biomedicines. 2020;8(8):E251. Published 2020 Jul 29.
- Signetti L, Elizarov N, Simsir M, Paquet A, Douguet D, Labbal F, Debayle D, Di Giorgio A, Biou V, Girard C, Duca M, Bretillon L, Bertolotto C, Verrier B, Azoulay S and Mus-Veteau I. Cancers (Basel), 2020, Inhibition Of Patched Drug Efflux Increases Vemurafenib Effectiveness Against Resistant BRAFV600E Melanoma. PMID: 32526884
- Hasanovic A, Mus-Veteau I. (2018) Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency. Cells. Aug 14;7(8). pii: E107. doi:10.3390/cells7080107. Review. PubMed PMID: 30110910; PubMed Central PMCID:PMC6115939.
- Hasanovic A, Ruggiero C, Jung S, Rapa I, Signetti L, Ben Hadj M, Terzolo M, Beuschlein F, Volante M, Hantel C, Lalli E, Mus-Veteau I. (2018) Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo. Int J Cancer. Jul 1;143(1):199-211. doi:10.1002/ijc.31296. Epub 2018 Feb 23. PubMed PMID: 29411361.
- Fiorini L, Tribalat M-A, Sauvard L, Cazareth J, Lalli E, Broutin I, Thomas O P & Mus-Veteau I. Oncotarget, 2015, Natural paniceins from Mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells. PMID: 26068979
| Session | Molecular interactions at the membrane surface |
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