Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic
The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting it...
| Autores: | , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/62969 |
| Acceso en línea: | https://hdl.handle.net/10171/62969 |
| Access Level: | acceso abierto |
| Palabra clave: | Selenium Isoselenourea Melanoma STAT3 Apoptosis |
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Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeuticAlcolea-Devesa, V. (Verónica)|||/items/cab0ef13-974a-41de-a2ef-387ee6a66179Karelia, D.N. (Deepkamal N.)|||/items/edf869ed-3e2f-4d4d-9c8e-25148aec02f6Pandey, M.K. (Manoj K.)|||/items/eb505420-f8a5-406f-9985-7e86ab23e7b1Plano-Amatriain, D. (Daniel)|||/items/238881e4-7d5e-4598-924d-4392e3b7e02eSingh, P. (Parvesh)|||/items/19da0f56-a508-4cb8-9818-194759fd680dPalop-Cubillo, J.A. (Juan Antonio)|||/items/bfa23090-c589-4aeb-89e5-bbe9aa243a90Amin, S. (Shantu)|||/items/b86c35fa-3721-497b-aefb-61241e844eb1Sanmartin-Grijalba, C. (Carmen)|||/items/d36bd105-ab64-427d-9745-5812cf5e7af7Sharma, A.K. (Arun K.)|||/items/60dd0409-6d27-487a-9afe-ef5167a4f185SeleniumIsoselenoureaMelanomaSTAT3ApoptosisThe prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032.MDPI AGDadun. Depósito Académico Digital Universidad de Navarra20222022-03-0220192019-01-0120192019-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/62969reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/629692026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic |
| title |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic |
| spellingShingle |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic Alcolea-Devesa, V. (Verónica)|||/items/cab0ef13-974a-41de-a2ef-387ee6a66179 Selenium Isoselenourea Melanoma STAT3 Apoptosis |
| title_short |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic |
| title_full |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic |
| title_fullStr |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic |
| title_full_unstemmed |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic |
| title_sort |
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic |
| dc.creator.none.fl_str_mv |
Alcolea-Devesa, V. (Verónica)|||/items/cab0ef13-974a-41de-a2ef-387ee6a66179 Karelia, D.N. (Deepkamal N.)|||/items/edf869ed-3e2f-4d4d-9c8e-25148aec02f6 Pandey, M.K. (Manoj K.)|||/items/eb505420-f8a5-406f-9985-7e86ab23e7b1 Plano-Amatriain, D. (Daniel)|||/items/238881e4-7d5e-4598-924d-4392e3b7e02e Singh, P. (Parvesh)|||/items/19da0f56-a508-4cb8-9818-194759fd680d Palop-Cubillo, J.A. (Juan Antonio)|||/items/bfa23090-c589-4aeb-89e5-bbe9aa243a90 Amin, S. (Shantu)|||/items/b86c35fa-3721-497b-aefb-61241e844eb1 Sanmartin-Grijalba, C. (Carmen)|||/items/d36bd105-ab64-427d-9745-5812cf5e7af7 Sharma, A.K. (Arun K.)|||/items/60dd0409-6d27-487a-9afe-ef5167a4f185 |
| author |
Alcolea-Devesa, V. (Verónica)|||/items/cab0ef13-974a-41de-a2ef-387ee6a66179 |
| author_facet |
Alcolea-Devesa, V. (Verónica)|||/items/cab0ef13-974a-41de-a2ef-387ee6a66179 Karelia, D.N. (Deepkamal N.)|||/items/edf869ed-3e2f-4d4d-9c8e-25148aec02f6 Pandey, M.K. (Manoj K.)|||/items/eb505420-f8a5-406f-9985-7e86ab23e7b1 Plano-Amatriain, D. (Daniel)|||/items/238881e4-7d5e-4598-924d-4392e3b7e02e Singh, P. (Parvesh)|||/items/19da0f56-a508-4cb8-9818-194759fd680d Palop-Cubillo, J.A. (Juan Antonio)|||/items/bfa23090-c589-4aeb-89e5-bbe9aa243a90 Amin, S. (Shantu)|||/items/b86c35fa-3721-497b-aefb-61241e844eb1 Sanmartin-Grijalba, C. (Carmen)|||/items/d36bd105-ab64-427d-9745-5812cf5e7af7 Sharma, A.K. (Arun K.)|||/items/60dd0409-6d27-487a-9afe-ef5167a4f185 |
| author_role |
author |
| author2 |
Karelia, D.N. (Deepkamal N.)|||/items/edf869ed-3e2f-4d4d-9c8e-25148aec02f6 Pandey, M.K. (Manoj K.)|||/items/eb505420-f8a5-406f-9985-7e86ab23e7b1 Plano-Amatriain, D. (Daniel)|||/items/238881e4-7d5e-4598-924d-4392e3b7e02e Singh, P. (Parvesh)|||/items/19da0f56-a508-4cb8-9818-194759fd680d Palop-Cubillo, J.A. (Juan Antonio)|||/items/bfa23090-c589-4aeb-89e5-bbe9aa243a90 Amin, S. (Shantu)|||/items/b86c35fa-3721-497b-aefb-61241e844eb1 Sanmartin-Grijalba, C. (Carmen)|||/items/d36bd105-ab64-427d-9745-5812cf5e7af7 Sharma, A.K. (Arun K.)|||/items/60dd0409-6d27-487a-9afe-ef5167a4f185 |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Selenium Isoselenourea Melanoma STAT3 Apoptosis |
| topic |
Selenium Isoselenourea Melanoma STAT3 Apoptosis |
| description |
The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 2019-01-01 2019 2019-01-01 2022 2022-03-02 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/62969 |
| url |
https://hdl.handle.net/10171/62969 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
MDPI AG |
| publisher.none.fl_str_mv |
MDPI AG |
| dc.source.none.fl_str_mv |
reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
| instname_str |
Universidad de Navarra |
| reponame_str |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
| collection |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
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1869412910829142016 |
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15,300719 |