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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

PCI-24781 alters the expression of the Ku86 protein. a PCI-24781 reduces the expression of the Ku86 protein, important for the repair of double-strand breaks caused by irradiation through the nonhomologous end joining (NHEJ) pathway. b Ratio between the Ku86 protein and endogenous GAPDH
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Fig8: PCI-24781 alters the expression of the Ku86 protein. a PCI-24781 reduces the expression of the Ku86 protein, important for the repair of double-strand breaks caused by irradiation through the nonhomologous end joining (NHEJ) pathway. b Ratio between the Ku86 protein and endogenous GAPDH

Mentions: The results showed that PCI-24781 was competent in reducing the efficiency of the SF188 line in diminishing the DSB induced by irradiation, with a reduction of the expression of the proteins tested. For the Ku 70, Ku 86 and DNA-PKcs proteins there was only a small difference between treatment with PCI-24781 alone or in combination (Figs. 7, 8, and 9 respectively). The most evident decrease was observed for the RAD51 protein, present in the HR pathway. For all proteins, treatment with PCI-24781 followed by 6 Gy of irradiation demonstrated the greatest inhibition of the repair pathway (Fig. 10).Fig. 7


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)

PCI-24781 alters the expression of the Ku86 protein. a PCI-24781 reduces the expression of the Ku86 protein, important for the repair of double-strand breaks caused by irradiation through the nonhomologous end joining (NHEJ) pathway. b Ratio between the Ku86 protein and endogenous GAPDH
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig8: PCI-24781 alters the expression of the Ku86 protein. a PCI-24781 reduces the expression of the Ku86 protein, important for the repair of double-strand breaks caused by irradiation through the nonhomologous end joining (NHEJ) pathway. b Ratio between the Ku86 protein and endogenous GAPDH
Mentions: The results showed that PCI-24781 was competent in reducing the efficiency of the SF188 line in diminishing the DSB induced by irradiation, with a reduction of the expression of the proteins tested. For the Ku 70, Ku 86 and DNA-PKcs proteins there was only a small difference between treatment with PCI-24781 alone or in combination (Figs. 7, 8, and 9 respectively). The most evident decrease was observed for the RAD51 protein, present in the HR pathway. For all proteins, treatment with PCI-24781 followed by 6 Gy of irradiation demonstrated the greatest inhibition of the repair pathway (Fig. 10).Fig. 7

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