Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy

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• 作者：Letizia Porcelli (1)
  Gabriella Guida (2)
  Anna E Quatrale (1)
  Tiziana Cocco (2)
  Letizia Sidella (1)
  Immacolata Maida (2)
  Rosa M Iacobazzi (1)
  Anna Ferretta (2)
  Diana A Stolfa (1)
  Sabino Strippoli (3)
  Stefania Guida (4)
  Stefania Tommasi (5)
  Michele Guida (3)
  Amalia Azzariti (1)
  
  1. Clinical and Preclinical Pharmacology Laboratory ; National Cancer Research Centre Istituto Tumori Giovanni Paolo II ; Viale O. Flacco ; 65 ; 70124 ; Bari ; Italy
  2. Department of Basic Medical Sciences ; Neurosciences and Sense Organs ; University of Bari ; P.zza Giulio Cesare ; 70124 ; Bari ; Italy
  3. Medical Oncology Department ; National Cancer Research Centre Istituto Tumori Giovanni Paolo II ; Viale O. Flacco ; 65 ; 70124 ; Bari ; Italy
  4. Unit of Dermatology and Venereology ; University of Bari ; P.zza Giulio Cesare ; 70124 ; Bari ; Italy
  5. Molecular Genetics Laboratory ; National Cancer Research Centre Istituto Tumori Giovanni Paolo II ; Viale O. Flacco ; 65 ; 70124 ; Bari ; Italy
  
• 关键词：Melanoma ; Barasertib ; Vemurafenib ; Nab ; paclitaxel ; BRAF status
• 刊名：Journal of Translational Medicine
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：13
• 期：1
• 全文大小：1,328 KB
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• 刊物主题：Biomedicine general; Medicine/Public Health, general;
• 出版者：BioMed Central
• ISSN：1479-5876

文摘

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.