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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 radiosensitizes the SF188 line. *p < 0.001. Data are reported as the mean ± standard deviation of three independent experiments. p values obtained by linear regression are shown for all cell lines (DMSO versus PCI-24781)
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Fig5: PCI-24781 radiosensitizes the SF188 line. *p < 0.001. Data are reported as the mean ± standard deviation of three independent experiments. p values obtained by linear regression are shown for all cell lines (DMSO versus PCI-24781)

Mentions: In order to determine the radiosensitizing effect of PCI-24781, the SF188 and KNS42 lines were treated with IC30 of the inhibitor, which was 0.25 µM for SF188 and 0.15 µM for KNS42, in combination with radiation at the doses of 0.5, 1, 2 and 4 Gy. It was observed that treatment with the inhibitor radiosensitized both cell lines, with a greater effect on the KNS42 line. The SF188 line showed a practically absent reduction of colony formation in the treatment with irradiation alone and a 45 % reduction with the combined treatment with PCI-24781 and the highest irradiation dose (Fig. 5). The KNS42 line showed a 20 % reduction of colony formation with irradiation alone and a 70 % reduction with the combined treatment with PCI-24781 and the highest irradiation dose (Fig. 6). Thus, treatment with PCI-24781 was able to sensitize strongly both lines to radiation.Fig. 5


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 radiosensitizes the SF188 line. *p < 0.001. Data are reported as the mean ± standard deviation of three independent experiments. p values obtained by linear regression are shown for all cell lines (DMSO versus PCI-24781)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: PCI-24781 radiosensitizes the SF188 line. *p < 0.001. Data are reported as the mean ± standard deviation of three independent experiments. p values obtained by linear regression are shown for all cell lines (DMSO versus PCI-24781)
Mentions: In order to determine the radiosensitizing effect of PCI-24781, the SF188 and KNS42 lines were treated with IC30 of the inhibitor, which was 0.25 µM for SF188 and 0.15 µM for KNS42, in combination with radiation at the doses of 0.5, 1, 2 and 4 Gy. It was observed that treatment with the inhibitor radiosensitized both cell lines, with a greater effect on the KNS42 line. The SF188 line showed a practically absent reduction of colony formation in the treatment with irradiation alone and a 45 % reduction with the combined treatment with PCI-24781 and the highest irradiation dose (Fig. 5). The KNS42 line showed a 20 % reduction of colony formation with irradiation alone and a 70 % reduction with the combined treatment with PCI-24781 and the highest irradiation dose (Fig. 6). Thus, treatment with PCI-24781 was able to sensitize strongly both lines to radiation.Fig. 5

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