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.
|Data di pubblicazione:||2015|
|Titolo:||Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy|
|Autori:||Porcelli, L.; Guida, G.; Quatrale, A.E.; Cocco, T.; Sidella, L.; Maida, I.; Iacobazzi, R.M.; Ferretta, A.; Stolfa, D.A.; Strippoli, S.; Guida, S.; Tommasi, S.; Guida, M.; Azzariti, A.|
|Digital Object Identifier (DOI):||10.1186/s12967-015-0385-4|
|Appare nelle tipologie:||Articolo su rivista|
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