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The histone deacetylase inhibitor PCI-24781 as a putative radiosensitizer in pediatric glioblastoma cell lines.

de Andrade PV, Andrade AF, de Paula Queiroz RG, Scrideli CA, Tone LG, Valera ET - Cancer Cell Int. (2016)

Bottom Line: Cell proliferation rates, clonogenicity and apoptosis were compared in the presence and absence of treatment with PCI-24781.We also compared the clonogenicity rates of the irradiated SF188 and KNS42 cell lines with or without previous treatment with PCI-24781 at the doses of 0.25-16 μM.The inhibitor blocked cell proliferation, induced death by apoptosis and reduced the colony forming capacity of the cell lines, both of them showing a significant decrease of colony formation at all irradiation doses.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Ribeirão Preto Medical School, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto-USP, University of São Paulo, 7º andar. Av. Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, SP CEP 14048-900 Brazil.

ABSTRACT

Background: Glioblastoma (GBM) is considered to be one of the most aggressive tumors of the central nervous system (CNS). Even with the use of modern treatment protocols, the prognosis remains reserved, with children with GBM having a mean survival of 12-15 months.

Methods: In the present study we investigated the potential radiosensitizing effect of PCI-24781, a potent pan-histone deacetylase inhibitor (HDACi), on the SF188 and KNS42 cell lines of pediatric GBM. Cell proliferation rates, clonogenicity and apoptosis were compared in the presence and absence of treatment with PCI-24781. We also compared the clonogenicity rates of the irradiated SF188 and KNS42 cell lines with or without previous treatment with PCI-24781 at the doses of 0.25-16 μM. In addition, we investigated the effects of PCI-24781 on the expression of some of the main proteins responsible for the repair of double-strand DNA breaks caused by irradiation.

Results: The inhibitor blocked cell proliferation, induced death by apoptosis and reduced the colony forming capacity of the cell lines, both of them showing a significant decrease of colony formation at all irradiation doses. The expression of the Rad51 protein, important for the homologous recombination (HR) repair pathway, and of the DNA-PKcs, Ku70 and Ku86 proteins, important for the non-homologous end joining (NHEJ) repair pathway, was more reduced when the irradiated cell line was previously treated with PCI-24781 than when it was treated exclusively with radiotherapy.

Conclusions: These findings demonstrate that HDACi PCI-24781 has a radiosensitizing profile that compromises the repair of double-strand DNA breaks in cells of pediatric GBM treated with radiotherapy.

No MeSH data available.


Related in: MedlinePlus

Percentage of annexin V-positive cells after treatment with PCI-24781 in the SF188 and KNS42 lines. *p < 0.05 for treated cells compared to control
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Fig3: Percentage of annexin V-positive cells after treatment with PCI-24781 in the SF188 and KNS42 lines. *p < 0.05 for treated cells compared to control

Mentions: We next investigated whether the reduction of cell proliferation observed was due to cell death by apoptosis. In order to determine if PCI-24781 induced apoptosis in cell lines of pediatric GBM we determined the percentage of apoptotic cells after labeling with annexin-V and propidium iodide (PI). Apoptosis was induced at 48 h at the doses of 2, 4, 8 and 16 µM in the pediatric GBM lines SF188 and KNS42. All doses tested showed a significant effect of increased apoptosis compared to control (p < 0.05). Starting at the 2 µM dose, the effect on the cell death rate of both lines was already quite significant compared to control, demonstrating that only a small dose of the PCI-24781 inhibitor was able to induce apoptosis. The cell death rate by apoptosis was almost 40 % for the SF188 line and 55 % for the KNS42 line at the maximum dose tested (Fig. 3).Fig. 3


The histone deacetylase inhibitor PCI-24781 as a putative radiosensitizer in pediatric glioblastoma cell lines.

de Andrade PV, Andrade AF, de Paula Queiroz RG, Scrideli CA, Tone LG, Valera ET - Cancer Cell Int. (2016)

Percentage of annexin V-positive cells after treatment with PCI-24781 in the SF188 and KNS42 lines. *p < 0.05 for treated cells compared to control
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835828&req=5

Fig3: Percentage of annexin V-positive cells after treatment with PCI-24781 in the SF188 and KNS42 lines. *p < 0.05 for treated cells compared to control
Mentions: We next investigated whether the reduction of cell proliferation observed was due to cell death by apoptosis. In order to determine if PCI-24781 induced apoptosis in cell lines of pediatric GBM we determined the percentage of apoptotic cells after labeling with annexin-V and propidium iodide (PI). Apoptosis was induced at 48 h at the doses of 2, 4, 8 and 16 µM in the pediatric GBM lines SF188 and KNS42. All doses tested showed a significant effect of increased apoptosis compared to control (p < 0.05). Starting at the 2 µM dose, the effect on the cell death rate of both lines was already quite significant compared to control, demonstrating that only a small dose of the PCI-24781 inhibitor was able to induce apoptosis. The cell death rate by apoptosis was almost 40 % for the SF188 line and 55 % for the KNS42 line at the maximum dose tested (Fig. 3).Fig. 3

Bottom Line: Cell proliferation rates, clonogenicity and apoptosis were compared in the presence and absence of treatment with PCI-24781.We also compared the clonogenicity rates of the irradiated SF188 and KNS42 cell lines with or without previous treatment with PCI-24781 at the doses of 0.25-16 μM.The inhibitor blocked cell proliferation, induced death by apoptosis and reduced the colony forming capacity of the cell lines, both of them showing a significant decrease of colony formation at all irradiation doses.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Ribeirão Preto Medical School, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto-USP, University of São Paulo, 7º andar. Av. Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, SP CEP 14048-900 Brazil.

ABSTRACT

Background: Glioblastoma (GBM) is considered to be one of the most aggressive tumors of the central nervous system (CNS). Even with the use of modern treatment protocols, the prognosis remains reserved, with children with GBM having a mean survival of 12-15 months.

Methods: In the present study we investigated the potential radiosensitizing effect of PCI-24781, a potent pan-histone deacetylase inhibitor (HDACi), on the SF188 and KNS42 cell lines of pediatric GBM. Cell proliferation rates, clonogenicity and apoptosis were compared in the presence and absence of treatment with PCI-24781. We also compared the clonogenicity rates of the irradiated SF188 and KNS42 cell lines with or without previous treatment with PCI-24781 at the doses of 0.25-16 μM. In addition, we investigated the effects of PCI-24781 on the expression of some of the main proteins responsible for the repair of double-strand DNA breaks caused by irradiation.

Results: The inhibitor blocked cell proliferation, induced death by apoptosis and reduced the colony forming capacity of the cell lines, both of them showing a significant decrease of colony formation at all irradiation doses. The expression of the Rad51 protein, important for the homologous recombination (HR) repair pathway, and of the DNA-PKcs, Ku70 and Ku86 proteins, important for the non-homologous end joining (NHEJ) repair pathway, was more reduced when the irradiated cell line was previously treated with PCI-24781 than when it was treated exclusively with radiotherapy.

Conclusions: These findings demonstrate that HDACi PCI-24781 has a radiosensitizing profile that compromises the repair of double-strand DNA breaks in cells of pediatric GBM treated with radiotherapy.

No MeSH data available.


Related in: MedlinePlus