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XAV939-mediated ARTD activity inhibition in human MB cell lines.

Renna C, Salaroli R, Cocchi C, Cenacchi G - PLoS ONE (2015)

Bottom Line: XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences.The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality.In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

ABSTRACT
Diphtheria toxin-like ADP-ribosyltransferases 1 and 5 (ARTD-1, ARTD-5) are poly ADP-ribose enzymes (PARP) involved in non-homologous end-joining (NHEJ), which is the major pathway of double-strand break (DSB) repair. In addition, ARTD-5, or Tankyrase (TNKS), is a positive regulator of the WNT signaling implicated in the development and biological behavior of many neoplasms, such as Medulloblastoma (MB), in which radiotherapy is an essential part of the treatment. The use of radiosensitizing agents may improve the therapeutic index in MB patients by increasing the efficacy of radiotherapy, while reducing toxicity to the neuroaxis. ARTD-5 seems to be a good molecular target for improving the current treatment of MB. In this study, we used the small molecule XAV939, a potent ARTD-5 inhibitor with a slight affinity for ARTD-1, in different human MB cell lines. XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences. The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality. In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients.

No MeSH data available.


Related in: MedlinePlus

XAV939 improves cell mortality IR-induced.Histograms represent means ± s.e. of three independent experiments. Mortality rates of XAV939 treated cells, IR treated cells, XAV939, and IR treated cells are reported as relative percentages compared to DMSO control cells. A. Cell mortality after a 2 Gy dose administration: XAV939 alone does not induce a significant cell mortality increase in each time point considered. The greatest cell death was observed in XAV939 and IR treated cells in both cell lines, with a statistically significant difference at 72 h and 96 h compared with IR treated cells (p <. 01 and p <. 05, respectively). B. Mortality rate in MB cell lines after two treatments with 2 Gy dose of IR. In both cell lines, cells treated with XAV939 and irradiated, as described, showed a double mortality rate compared to DMSO irradiated cells (p <. 001).
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pone.0124149.g004: XAV939 improves cell mortality IR-induced.Histograms represent means ± s.e. of three independent experiments. Mortality rates of XAV939 treated cells, IR treated cells, XAV939, and IR treated cells are reported as relative percentages compared to DMSO control cells. A. Cell mortality after a 2 Gy dose administration: XAV939 alone does not induce a significant cell mortality increase in each time point considered. The greatest cell death was observed in XAV939 and IR treated cells in both cell lines, with a statistically significant difference at 72 h and 96 h compared with IR treated cells (p <. 01 and p <. 05, respectively). B. Mortality rate in MB cell lines after two treatments with 2 Gy dose of IR. In both cell lines, cells treated with XAV939 and irradiated, as described, showed a double mortality rate compared to DMSO irradiated cells (p <. 001).

Mentions: DAOY cells irradiated with a 2 Gy dose showed a 16.81%, 10.9%, and 9.3% mortality rate at 48, 72, and 96 h after radiation, respectively. Cells treated with 5 μM of XAV939 before IR showed 23.5%, 17%, and 13% mortality rate with a 6.77%, 6.1%, and 3.7% increase (data not shown). Normalizing data to controls, we observed, at 72 h and 96 h after radiation, about a 40% and a 45% increase in cell mortality in cells pre-treated with XAV939 compared to only irradiated ones (Fig 4A): this difference was considered statistically significant (p <. 01 and p <. 05, respectively, one-way ANOVA). ONS-76 cells, at the same time points, showed a 10.61%, 9.11%, and 10.43% mortality rate after IR. In this cell line, XAV939 induced a slight increase in IR-mediated cell mortality: 12.96%, 13.49%, and 13.23% with a difference of 2.35%, 4.38%, and 2.8%, respectively (data not shown). When we normalized data to controls, a statistically significant increase in cell mortality between IR treated cells, XAV939, and irradiated cells was observed at 72 h (52.8%, p <. 01 one-way ANOVA) and at 96 h (30%, p <. 05, one-way ANOVA).


XAV939-mediated ARTD activity inhibition in human MB cell lines.

Renna C, Salaroli R, Cocchi C, Cenacchi G - PLoS ONE (2015)

XAV939 improves cell mortality IR-induced.Histograms represent means ± s.e. of three independent experiments. Mortality rates of XAV939 treated cells, IR treated cells, XAV939, and IR treated cells are reported as relative percentages compared to DMSO control cells. A. Cell mortality after a 2 Gy dose administration: XAV939 alone does not induce a significant cell mortality increase in each time point considered. The greatest cell death was observed in XAV939 and IR treated cells in both cell lines, with a statistically significant difference at 72 h and 96 h compared with IR treated cells (p <. 01 and p <. 05, respectively). B. Mortality rate in MB cell lines after two treatments with 2 Gy dose of IR. In both cell lines, cells treated with XAV939 and irradiated, as described, showed a double mortality rate compared to DMSO irradiated cells (p <. 001).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383513&req=5

pone.0124149.g004: XAV939 improves cell mortality IR-induced.Histograms represent means ± s.e. of three independent experiments. Mortality rates of XAV939 treated cells, IR treated cells, XAV939, and IR treated cells are reported as relative percentages compared to DMSO control cells. A. Cell mortality after a 2 Gy dose administration: XAV939 alone does not induce a significant cell mortality increase in each time point considered. The greatest cell death was observed in XAV939 and IR treated cells in both cell lines, with a statistically significant difference at 72 h and 96 h compared with IR treated cells (p <. 01 and p <. 05, respectively). B. Mortality rate in MB cell lines after two treatments with 2 Gy dose of IR. In both cell lines, cells treated with XAV939 and irradiated, as described, showed a double mortality rate compared to DMSO irradiated cells (p <. 001).
Mentions: DAOY cells irradiated with a 2 Gy dose showed a 16.81%, 10.9%, and 9.3% mortality rate at 48, 72, and 96 h after radiation, respectively. Cells treated with 5 μM of XAV939 before IR showed 23.5%, 17%, and 13% mortality rate with a 6.77%, 6.1%, and 3.7% increase (data not shown). Normalizing data to controls, we observed, at 72 h and 96 h after radiation, about a 40% and a 45% increase in cell mortality in cells pre-treated with XAV939 compared to only irradiated ones (Fig 4A): this difference was considered statistically significant (p <. 01 and p <. 05, respectively, one-way ANOVA). ONS-76 cells, at the same time points, showed a 10.61%, 9.11%, and 10.43% mortality rate after IR. In this cell line, XAV939 induced a slight increase in IR-mediated cell mortality: 12.96%, 13.49%, and 13.23% with a difference of 2.35%, 4.38%, and 2.8%, respectively (data not shown). When we normalized data to controls, a statistically significant increase in cell mortality between IR treated cells, XAV939, and irradiated cells was observed at 72 h (52.8%, p <. 01 one-way ANOVA) and at 96 h (30%, p <. 05, one-way ANOVA).

Bottom Line: XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences.The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality.In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

ABSTRACT
Diphtheria toxin-like ADP-ribosyltransferases 1 and 5 (ARTD-1, ARTD-5) are poly ADP-ribose enzymes (PARP) involved in non-homologous end-joining (NHEJ), which is the major pathway of double-strand break (DSB) repair. In addition, ARTD-5, or Tankyrase (TNKS), is a positive regulator of the WNT signaling implicated in the development and biological behavior of many neoplasms, such as Medulloblastoma (MB), in which radiotherapy is an essential part of the treatment. The use of radiosensitizing agents may improve the therapeutic index in MB patients by increasing the efficacy of radiotherapy, while reducing toxicity to the neuroaxis. ARTD-5 seems to be a good molecular target for improving the current treatment of MB. In this study, we used the small molecule XAV939, a potent ARTD-5 inhibitor with a slight affinity for ARTD-1, in different human MB cell lines. XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences. The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality. In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients.

No MeSH data available.


Related in: MedlinePlus