Revistas
Revista:
INTERNATIONAL JOURNAL OF ONCOLOGY
ISSN:
1019-6439
Año:
2021
Vol.:
58
N°:
3
Págs.:
312 - 330
Glioblastoma is the most malignant brain tumor and presents high resistance to chemotherapy and radiotherapy. Surgery, radiotherapy and chemotherapy with temozolomide are the only treatments against this tumor. New targeted therapies, including epigenetic modulators such as 3-deazane-planocin A (DZ-Nep; an EZH2 inhibitor) and panobinostat (a histone deacetylase inhibitor) are being tested in vitro, together with temozolomide. The present study combined APR-246 with DZ-Nep, panobinostat and teomozolomide in order to explore the possibility of restoring p53 function in mutated cases of glioblastoma. Following the Chou-Talalay method it was demonstrated that APR-246 acts in an additive manner together with the other compounds, reducing clonogenicity and inducing apoptosis in glioblastoma cells independently of p53 status.
Revista:
GLIOMA
ISSN:
2589-6113
Año:
2021
Vol.:
4
N°:
2
Págs.:
27 - 33
Background and Aim: Glioblastoma is the most lethal brain tumor. No effective curative treatment is available yet, and it is treated by surgery,
temozolomide (TMZ), and radiotherapy, with an average overall survival of around 15 months. Inhibitors of histone deacetylases (HDACs)
are being explored against a variety of tumors, including glioblastoma. Specific inhibitors of HDAC6, such as tubastatin A (Tub A), may
potentially be beneficial as HDAC6 has been demonstrated to be the most expressed HDACs in glioblastoma. Our aim was to test whether
Tub A could reverse the malignant phenotype of U87MG cells via the inhibition of HDAC6. Materials and Methods: U87MG cells were
treated with cyclopamine (Cyp), TMZ, and Tub A. Two double treatments were performed as well (Cyp + Tub A and TMZ + Tub A). Colony
formation, wound healing, Caspase¿Glo 3/7, quantitative reverse transcription¿polymerase chain reaction, luciferase assay, and Western blot
assays were conducted to determine clonogenic and migration capacity, apoptosis, activation of the Sonic Hedgehog pathway, acetylation of
¿¿tubulin and epithelial-to-mesenchymal transition, and autophagic flux of U87MG glioblastoma cells, respectively. Results: Tub A treatment
caused a reversal of the U87MG malignant phenotype by reducing its clonogenic and migratory cellular potential, and inducing apoptosis.
Revista:
BIOLOGY
ISSN:
2079-7737
Año:
2021
Vol.:
10
N°:
6
Págs.:
467
Simple Summary Glioblastoma multiforme (GBM) is the most common as well as the most aggressive malignant brain tumor, with an overall survival of almost 15 months. Histone deacetylase 6 (HDAC6), an enzyme related to the deacetylation of alpha-tubulin, is overexpressed in GBM. The aim of our research was to study the effects of HDAC6 silencing in GBM cells. We first confirmed the overexpression of HDAC6 in GBM tissue (n = 40) against control brain (n = 10). Treatment with siHDAC6 diminished viability, clonogenic potential, and migration ability in GBM-derived cell lines. HDAC6 inhibition also reverted the mesenchymal phenotype, inhibited the Sonic Hedgehog pathway, restored primary cilium structure, and decreased autophagy. Thus, we confirm that HDAC6 is a good therapeutic target for GBM treatment. Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor.
Revista:
INTERNATIONAL JOURNAL OF ONCOLOGY
ISSN:
1019-6439
Año:
2020
Vol.:
56
N°:
1
Págs.:
283 - 300
Current treatment against glioblastoma consists of surgical resection followed by temozolomide, with or without combined radiotherapy. Glioblastoma frequently acquires resistance to chemotherapy and/or radiotherapy. Novel therapeutic approaches are thus required. The inhibition of enhancer of zeste homolog 2 (EZH2; a histone methylase) and histone deacetylases (HDACs) are possible epigenetic treatments. Temozolomide, 3-deazaneplanocin A (DZ-Nep; an EZH2 inhibitor) and panobinostat (an HDAC inhibitor) were tested in regular and temozolomide-resistant glioblastoma cells to confirm whether the compounds could behave in a synergistic, additive or antagonistic manner. A total of six commercial cell lines, two temozolomide-induced resistant cell lines and two primary cultures derived from glioblastoma samples were used. Cell lines were exposed to single treatments of the drugs in addition to all possible two-and three-drug combinations. Colony formation assays, synergistic assays and reverse transcription-quantitative PCR analysis of apoptosis-associated genes were performed. The highest synergistic combination was DZ-Nep + panobinostat. Triple treatment was also synergistic. Reduced clonogenicity and increased apoptosis were both induced. It was concluded that the therapeutic potential of the combination of these three drugs in glioblastoma was evident and should be further explored.
Revista:
INTERNATIONAL JOURNAL OF ONCOLOGY
ISSN:
1019-6439
Año:
2019
Vol.:
54
N°:
5
Págs.:
1797 - 1808
Glioblastoma or grade IV astrocytoma is the most common and lethal form of glioma. Current glioblastoma treatment strategies use surgery followed by chemotherapy with temozolomide. Despite this, numerous glioblastoma cases develop resistance to temozolomide treatments, resulting in a poor prognosis for the patients. Novel approaches are being investigated, including the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates a-tubulin, and whose overexpression in glioblastoma is associated with the loss of primary cilia. The aim of the present study was to treat glioblastoma cells with a selective HDAC6 inhibitor, tubastatin A, to determine if the malignant phenotype may be reverted. The results demonstrated a notable increase in acetylated a-tubulin levels in treated cells, which associated with downregulation of the sonic hedgehog pathway, and may hypothetically promote ciliogenesis in those cells. Treatment with tubastatin A also reduced glioblastoma clonogenicity and migration capacities, and accelerated temozolomide-induced apoptosis. Finally, HDAC6 inhibition decreased the expression of mesenchymal markers, contributing to reverse epithelial-mesenchymal transition in glioblastoma cells.
Revista:
GLIOMA
ISSN:
2589-6113
Año:
2018
Vol.:
1
N°:
1
Págs.:
22 - 26
Background: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. Current treatment against this tumor consists of maximal surgical resection without threatening the patient's life, followed by a treatment with temozolomide, with or without combined radiotherapy. GBM is resistant to the conventional antitumor therapies, so in this research, we tried to inhibit tumor growth with the combination of three drugs: (1) panobinostat, an inhibitor of histone deacetylases, (2) 3-Dezaneplanocin-A (DZNep), an inhibitor of EZH2, a protein which belongs to the polycomb repressor complex 2, acting as a histone methylase, and (3) temozolomide, an alkylating agent. Methods: The T98G GBM commercial cell line was used. Cells were exposed to single treatments of the drugs and to the three possible combinations among them. Soon after, two-dimensional (2D) and 3D clonogenic assays were assessed for in vitro tumorigenicity testing. Real-time quantitative polymerase chain reaction of 2 proapoptotic genes (BAX and NOXA) and 2 antiapoptotic genes (BCL2 and BCL-XL) was also assessed. Results: The panobinostat and temozolomide combination produced a positive effect against T98G glioblastoma cells by reducing soft agar colony formation, by inducing high expression levels of NOXA, and by reducing BCL-XL expression.
Revista:
CANCER TRANSLATIONAL MEDICINE
ISSN:
2395-3012
Año:
2018
Vol.:
4
N°:
5
Págs.:
39 - 47
Revista:
EPIGENOMES
ISSN:
2075-4655
Glioblastoma is the most common form of glioma, as well as the most aggressive. Patients suffering from this disease have a very poor prognosis. Surgery, radiotherapy, and temozolomide are the only approved treatments nowadays. Panobinostat is a pan-inhibitor of histone deacetylases (HDACs) that has been shown to break some pathways which play an important role in cancer development. A global intention of using panobinostat as a therapeutic agent against glioblastoma is beginning to be a reality. We have treated the LN405 glioblastoma cell line with temozolomide, panobinostat, and combined treatment, in order to test apoptosis, colony formation, and a possible molecular reversion of the mesenchymal phenotype of the cells to an epithelial one. Our results show that panobinostat decreased N-cadherin levels in the LN405 glioblastoma cell line while it increased the expression of E-cadherin, which might be associated with a mesenchymal-epithelial transition in glioblastoma cells. Colony formation was reduced, and apoptosis was increased with treatments. Our research highlights the importance of panobinostat as a potential adjuvant therapy to be used with temozolomide to treat glioblastoma and the advantages of the combined treatment versus temozolomide alone, which is currently the first-line treatment used to treat this tumor.
Otros (PIUNA, fundaciones, contratos…)
Título:
Moduladores epigenéticos y promotores del cilio primario como nuevos agentes terapéuticos contra el glioblastoma
Código de expediente:
2018-22
Financiador:
UNIVERSIDAD DE NAVARRA
Convocatoria:
2020 Convocatoria PIUNA
Fecha de inicio:
01/09/2018
Fecha fin:
31/08/2021
Importe concedido:
11.000,00€