AI Article Synopsis
Article 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314759 | PMC |
| http://dx.doi.org/10.1186/s12967-015-0385-4 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Advancing therapeutic frontiers: a pipeline of novel drugs for luminal and perianal Crohn's disease management.
Therap Adv Gastroenterol
December 2024
Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, Padua 35128, Italy.
Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria.
View Article and Find Full Text PDFThe aberrantly activated AURKB supports and complements the function of AURKA in CALR mutated cells through regulating the cell growth and differentiation.
Exp Cell Res
December 2024
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China. Electronic address:
Aurora kinase B (AURKB) was reported to assist Aurora kinase A (AURKA) to regulate cellular mitosis. AURKA has been found activated in myeloproliferative neoplasms (MPNs) patients with CALR gene mutation, however, it's unclear whether AURKB displays a compensatory function of AURKA in regulation of CALR mutant cell growth and differentiation. Here, we found that AURKB, similar with AURKA, was aberrantly activated in CALR mutant patients, and displayed a more tolerance to the aurora kinase inhibitor.
View Article and Find Full Text PDFDeSUMOylating isopeptidase 1 participates in the faithful chromosome segregation and vincristine sensitivity.
FASEB J
December 2024
Laboratory of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan.
SUMOylation, the modification of proteins with a small ubiquitin-like modifier (SUMO), is known to regulate various cellular events, including cell division. This process is dynamic, with its status depending on the balance between SUMOylation and deSUMOylation. While the regulation of cell division by sentrin-specific protease (SENP) family proteins through deSUMOylation has been investigated, the role of another deSUMOylase, deSUMOylating isopeptidase 1 (DESI1), remains unknown.
View Article and Find Full Text PDFDistinct roles of centriole distal appendage proteins in ciliary assembly and disassembly.
Cell Commun Signal
December 2024
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
The primary cilium is a cellular organelle whose assembly and disassembly are closely linked to the cell cycle. The centriole distal appendage (DA) is essential for the early stages of ciliogenesis by anchoring the mother centriole to the cell surface. Despite the identification of over twelve proteins constituting the DA, including CEP83, CEP89, CEP164, FBF1, and SCLT1, their specific functions in ciliary dynamics are not fully understood.
View Article and Find Full Text PDFRNPS1 in PSAP complex controls periodic pre-mRNA splicing over the cell cycle.
iScience
December 2024
Division of Gene Regulation, Oncology Innovation Center, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Cell cycle progression requires periodic gene expression through splicing control. However, the splicing factor that directly controls this cell cycle-dependent splicing remains unknown. Cell cycle-dependent expression of the (aurora kinase B) gene is essential for chromosome segregation and cytokinesis.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!