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

Autor: Anna Elisa Quatrale, Immacolata Maida, Tiziana Cocco, Gabriella Guida, Michele Guida, Sabino Strippoli, Diana A Stolfa, Amalia Azzariti, Stefania Tommasi, Stefania Guida, Letizia Sidella, Rosa Maria Iacobazzi, Letizia Porcelli, Anna Ferretta
Jazyk: angličtina
Předmět:
Proto-Oncogene Proteins B-raf
Cell Nucleus Shape
Paclitaxel
Cell Survival
Aurora B kinase
Mitosis
Apoptosis
Nab-paclitaxel
Gene mutation
Biology
General Biochemistry
Genetics and Molecular Biology
Necrosis
Cell Movement
Albumins
Cell Line
Tumor
medicine
Aurora Kinase B
Humans
Barasertib
Lactic Acid
Neoplasm Metastasis
Vemurafenib
Melanoma
Cell Shape
Protein Kinase Inhibitors
Mitotic catastrophe
Cell Proliferation
Medicine(all)
Cell growth
Biochemistry
Genetics and Molecular Biology(all)
Research
aurora B kinase
B Raf kinase
barasertib
lactic acid
microphthalmia associated transcription factor
mitogen activated protein kinase 1
mitogen activated protein kinase 3
mitogen activated protein kinase p38
paclitaxel
vemurafenib
antiproliferative activity
apoptosis
Article
cancer combination chemotherapy
cancer inhibition
cell cycle progression
cell death
cell migration
cell proliferation
concentration response
controlled study
drug efficacy
drug potentiation
drug resistance
drug response
drug sensitivity
enzyme activation
enzyme inhibition
gene mutation
glycolysis
IC50
in vitro study
long term exposure
melanoma cell line
metastatic melanoma
monotherapy
mutant
protein expression
wild type
BRAF status
Cell migration
General Medicine
medicine.disease
Organophosphates
Drug Resistance
Neoplasm
Quinazolines
Cancer research
Extracellular Space
medicine.drug
Zdroj: Journal of Translational Medicine
ISSN: 1479-5876
DOI: 10.1186/s12967-015-0385-4
Popis: 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. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0385-4) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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