Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy
Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it...
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| Autor*in: |
Porcelli, Letizia [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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© Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
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| Übergeordnetes Werk: |
Enthalten in: Journal of translational medicine - London : BioMed Central, 2003, 13(2015), 1 vom: 27. Jan. |
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| Übergeordnetes Werk: |
volume:13 ; year:2015 ; number:1 ; day:27 ; month:01 |
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| DOI / URN: |
10.1186/s12967-015-0385-4 |
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SPR028954637 |
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| 520 | |a Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. | ||
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| 650 | 4 | |a Vemurafenib |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Nab-paclitaxel |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a BRAF status |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Guida, Gabriella |4 aut | |
| 700 | 1 | |a Quatrale, Anna E |4 aut | |
| 700 | 1 | |a Cocco, Tiziana |4 aut | |
| 700 | 1 | |a Sidella, Letizia |4 aut | |
| 700 | 1 | |a Maida, Immacolata |4 aut | |
| 700 | 1 | |a Iacobazzi, Rosa M |4 aut | |
| 700 | 1 | |a Ferretta, Anna |4 aut | |
| 700 | 1 | |a Stolfa, Diana A |4 aut | |
| 700 | 1 | |a Strippoli, Sabino |4 aut | |
| 700 | 1 | |a Guida, Stefania |4 aut | |
| 700 | 1 | |a Tommasi, Stefania |4 aut | |
| 700 | 1 | |a Guida, Michele |4 aut | |
| 700 | 1 | |a Azzariti, Amalia |4 aut | |
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10.1186/s12967-015-0385-4 doi (DE-627)SPR028954637 (SPR)s12967-015-0385-4-e DE-627 ger DE-627 rakwb eng Porcelli, Letizia verfasserin aut Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. Melanoma (dpeaa)DE-He213 Barasertib (dpeaa)DE-He213 Vemurafenib (dpeaa)DE-He213 Nab-paclitaxel (dpeaa)DE-He213 BRAF status (dpeaa)DE-He213 Guida, Gabriella aut Quatrale, Anna E aut Cocco, Tiziana aut Sidella, Letizia aut Maida, Immacolata aut Iacobazzi, Rosa M aut Ferretta, Anna aut Stolfa, Diana A aut Strippoli, Sabino aut Guida, Stefania aut Tommasi, Stefania aut Guida, Michele aut Azzariti, Amalia aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 13(2015), 1 vom: 27. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:13 year:2015 number:1 day:27 month:01 https://dx.doi.org/10.1186/s12967-015-0385-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2015 1 27 01 |
| spelling |
10.1186/s12967-015-0385-4 doi (DE-627)SPR028954637 (SPR)s12967-015-0385-4-e DE-627 ger DE-627 rakwb eng Porcelli, Letizia verfasserin aut Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. Melanoma (dpeaa)DE-He213 Barasertib (dpeaa)DE-He213 Vemurafenib (dpeaa)DE-He213 Nab-paclitaxel (dpeaa)DE-He213 BRAF status (dpeaa)DE-He213 Guida, Gabriella aut Quatrale, Anna E aut Cocco, Tiziana aut Sidella, Letizia aut Maida, Immacolata aut Iacobazzi, Rosa M aut Ferretta, Anna aut Stolfa, Diana A aut Strippoli, Sabino aut Guida, Stefania aut Tommasi, Stefania aut Guida, Michele aut Azzariti, Amalia aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 13(2015), 1 vom: 27. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:13 year:2015 number:1 day:27 month:01 https://dx.doi.org/10.1186/s12967-015-0385-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2015 1 27 01 |
| allfields_unstemmed |
10.1186/s12967-015-0385-4 doi (DE-627)SPR028954637 (SPR)s12967-015-0385-4-e DE-627 ger DE-627 rakwb eng Porcelli, Letizia verfasserin aut Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. Melanoma (dpeaa)DE-He213 Barasertib (dpeaa)DE-He213 Vemurafenib (dpeaa)DE-He213 Nab-paclitaxel (dpeaa)DE-He213 BRAF status (dpeaa)DE-He213 Guida, Gabriella aut Quatrale, Anna E aut Cocco, Tiziana aut Sidella, Letizia aut Maida, Immacolata aut Iacobazzi, Rosa M aut Ferretta, Anna aut Stolfa, Diana A aut Strippoli, Sabino aut Guida, Stefania aut Tommasi, Stefania aut Guida, Michele aut Azzariti, Amalia aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 13(2015), 1 vom: 27. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:13 year:2015 number:1 day:27 month:01 https://dx.doi.org/10.1186/s12967-015-0385-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2015 1 27 01 |
| allfieldsGer |
10.1186/s12967-015-0385-4 doi (DE-627)SPR028954637 (SPR)s12967-015-0385-4-e DE-627 ger DE-627 rakwb eng Porcelli, Letizia verfasserin aut Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. Melanoma (dpeaa)DE-He213 Barasertib (dpeaa)DE-He213 Vemurafenib (dpeaa)DE-He213 Nab-paclitaxel (dpeaa)DE-He213 BRAF status (dpeaa)DE-He213 Guida, Gabriella aut Quatrale, Anna E aut Cocco, Tiziana aut Sidella, Letizia aut Maida, Immacolata aut Iacobazzi, Rosa M aut Ferretta, Anna aut Stolfa, Diana A aut Strippoli, Sabino aut Guida, Stefania aut Tommasi, Stefania aut Guida, Michele aut Azzariti, Amalia aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 13(2015), 1 vom: 27. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:13 year:2015 number:1 day:27 month:01 https://dx.doi.org/10.1186/s12967-015-0385-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2015 1 27 01 |
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10.1186/s12967-015-0385-4 doi (DE-627)SPR028954637 (SPR)s12967-015-0385-4-e DE-627 ger DE-627 rakwb eng Porcelli, Letizia verfasserin aut Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. Melanoma (dpeaa)DE-He213 Barasertib (dpeaa)DE-He213 Vemurafenib (dpeaa)DE-He213 Nab-paclitaxel (dpeaa)DE-He213 BRAF status (dpeaa)DE-He213 Guida, Gabriella aut Quatrale, Anna E aut Cocco, Tiziana aut Sidella, Letizia aut Maida, Immacolata aut Iacobazzi, Rosa M aut Ferretta, Anna aut Stolfa, Diana A aut Strippoli, Sabino aut Guida, Stefania aut Tommasi, Stefania aut Guida, Michele aut Azzariti, Amalia aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 13(2015), 1 vom: 27. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:13 year:2015 number:1 day:27 month:01 https://dx.doi.org/10.1186/s12967-015-0385-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2015 1 27 01 |
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Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy |
| abstract |
Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
| abstractGer |
Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
| abstract_unstemmed |
Background The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment. © Porcelli et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
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Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy |
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Guida, Gabriella Quatrale, Anna E Cocco, Tiziana Sidella, Letizia Maida, Immacolata Iacobazzi, Rosa M Ferretta, Anna Stolfa, Diana A Strippoli, Sabino Guida, Stefania Tommasi, Stefania Guida, Michele Azzariti, Amalia |
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Guida, Gabriella Quatrale, Anna E Cocco, Tiziana Sidella, Letizia Maida, Immacolata Iacobazzi, Rosa M Ferretta, Anna Stolfa, Diana A Strippoli, Sabino Guida, Stefania Tommasi, Stefania Guida, Michele Azzariti, Amalia |
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