Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> Melanoma
Melanoma patients harboring the BRAF<sup>V600E</sup> mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of B...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/6/1500 |
| _version_ | 1797565773066010624 |
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| author | Laurie Signetti Nelli Elizarov Méliné Simsir Agnès Paquet Dominique Douguet Fabien Labbal Delphine Debayle Audrey Di Giorgio Valérie Biou Christophe Girard Maria Duca Lionel Bretillon Corine Bertolotto Bernard Verrier Stéphane Azoulay Isabelle Mus-Veteau |
| author_facet | Laurie Signetti Nelli Elizarov Méliné Simsir Agnès Paquet Dominique Douguet Fabien Labbal Delphine Debayle Audrey Di Giorgio Valérie Biou Christophe Girard Maria Duca Lionel Bretillon Corine Bertolotto Bernard Verrier Stéphane Azoulay Isabelle Mus-Veteau |
| author_sort | Laurie Signetti |
| collection | DOAJ |
| description | Melanoma patients harboring the BRAF<sup>V600E</sup> mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAF<sup>V600E</sup> melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that 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 PAH is a highly promising lead for the treatment of vemurafenib resistant BRAF<sup>V600E</sup> melanoma. |
| first_indexed | 2024-03-10T19:16:47Z |
| format | Article |
| id | doaj.art-322b7310349241eaa8db7ae749f4accc |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:16:47Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-322b7310349241eaa8db7ae749f4accc2023-11-20T03:16:55ZengMDPI AGCancers2072-66942020-06-01126150010.3390/cancers12061500Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> MelanomaLaurie Signetti0Nelli Elizarov1Méliné Simsir2Agnès Paquet3Dominique Douguet4Fabien Labbal5Delphine Debayle6Audrey Di Giorgio7Valérie Biou8Christophe Girard9Maria Duca10Lionel Bretillon11Corine Bertolotto12Bernard Verrier13Stéphane Azoulay14Isabelle Mus-Veteau15Université Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, FranceUniversité Côte d’Azur, CNRS, ICN, 28 Avenue Valrose, 06108 Nice, CEDEX 2, FranceUniversité Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, FranceUniversité Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, FranceUniversité Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, FranceUniversité Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, FranceUniversité Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, FranceUniversité Côte d’Azur, CNRS, ICN, 28 Avenue Valrose, 06108 Nice, CEDEX 2, FranceCNRS, IBPC, Sorbonne Paris Cité, Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, Institut de Biologie Physico-Chimique, University Paris Diderot, 13 rue Pierre et Marie Curie, 75005 Paris, FranceUniversité Côte d’Azur, INSERM, CNRS, C3M, Bâtiment Universitaire ARCHIMED 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, CEDEX 3, FranceUniversité Côte d’Azur, CNRS, ICN, 28 Avenue Valrose, 06108 Nice, CEDEX 2, FranceCentre des Sciences du Goût et de l’Alimentation, Université Bourgogne Franche-Comté CNRS, INRA, SSGA, AgroSup Dijon, F-21000 Dijon, FranceUniversité Côte d’Azur, INSERM, CNRS, C3M, Bâtiment Universitaire ARCHIMED 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, CEDEX 3, FranceAdjuvatis SAS, IBCP, 7 Passage du Vercors—69007 Lyon, FranceUniversité Côte d’Azur, CNRS, ICN, 28 Avenue Valrose, 06108 Nice, CEDEX 2, FranceUniversité Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, FranceMelanoma patients harboring the BRAF<sup>V600E</sup> mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAF<sup>V600E</sup> melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that 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 PAH is a highly promising lead for the treatment of vemurafenib resistant BRAF<sup>V600E</sup> melanoma.https://www.mdpi.com/2072-6694/12/6/1500Patchedmelanomavemurafenibchemotherapy resistance: drug effluxnew therapeutic lead |
| spellingShingle | Laurie Signetti Nelli Elizarov Méliné Simsir Agnès Paquet Dominique Douguet Fabien Labbal Delphine Debayle Audrey Di Giorgio Valérie Biou Christophe Girard Maria Duca Lionel Bretillon Corine Bertolotto Bernard Verrier Stéphane Azoulay Isabelle Mus-Veteau Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> Melanoma Cancers Patched melanoma vemurafenib chemotherapy resistance: drug efflux new therapeutic lead |
| title | Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> Melanoma |
| title_full | Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> Melanoma |
| title_fullStr | Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> Melanoma |
| title_full_unstemmed | Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> Melanoma |
| title_short | Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant Braf<sup>V600E</sup> Melanoma |
| title_sort | inhibition of patched drug efflux increases vemurafenib effectiveness against resistant braf sup v600e sup melanoma |
| topic | Patched melanoma vemurafenib chemotherapy resistance: drug efflux new therapeutic lead |
| url | https://www.mdpi.com/2072-6694/12/6/1500 |
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