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Administration of ON 01210.Na after exposure to ionizing radiation protects bone marrow cells by attenuating DNA damage response.

Suman S, Maniar M, Fornace AJ, Datta K - Radiat Oncol (2012)

Bottom Line: Post-irradiation treatment of mice with ON 01210.Na also resulted in higher GM-CFU counts.The mitigation effects were accompanied by attenuation of ATM-p53-dependent DNA damage response in the bone marrow cells of ON 01210.Na treated mice.Both phospho-ATM and phospho-p53 were significantly lower in the bone marrow cells of ON 01210.Na treated than in vehicle treated mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular & Cell Biology, Georgetown University Medical Center, Research Building, Room E518, 3970 Reservoir Rd., NW, Washington, DC 20057-1468, USA.

ABSTRACT

Background: Ionizing radiation-induced hematopoietic injury could occur either due to accidental exposure or due to diagnostic and therapeutic interventions. Currently there is no approved drug to mitigate radiation toxicity in hematopoietic cells. This study investigates the potential of ON 01210.Na, a chlorobenzylsulfone derivative, in ameliorating radiation-induced hematopoietic toxicity when administered after exposure to radiation. We also investigate the molecular mechanisms underlying this activity.

Methods: Male C3H/HeN mice (n = 5 mice per group; 6-8 weeks old) were exposed to a sub-lethal dose (5 Gy) of γ radiation using a ¹³⁷Cs source at a dose rate of 0.77 Gy/min. Two doses of ON 01210.Na (500 mg/kg body weight) were administered subcutaneously at 24 h and 36 h after radiation exposure. Mitigation of hematopoietic toxicity by ON 01210.Na was investigated by peripheral white blood cell (WBC) and platelet counts at 3, 7, 21, and 28 d after radiation exposure. Granulocyte macrophage colony forming unit (GM-CFU) assay was done using isolated bone marrow cells, and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) was performed on bone marrow sections at 7 d post-exposure. The DNA damage response pathway involving ataxia telangiectasia mutated (ATM) and p53 was investigated by Western blot in bone marrow cells at 7 d post-exposure.

Results: Compared to the vehicle, ON 01210.Na treated mice showed accelerated recovery of peripheral WBC and platelet counts. Post-irradiation treatment of mice with ON 01210.Na also resulted in higher GM-CFU counts. The mitigation effects were accompanied by attenuation of ATM-p53-dependent DNA damage response in the bone marrow cells of ON 01210.Na treated mice. Both phospho-ATM and phospho-p53 were significantly lower in the bone marrow cells of ON 01210.Na treated than in vehicle treated mice. Furthermore, the Bcl2:Bax ratio was higher in the drug treated mice than the vehicle treated groups.

Conclusions: ON 01210.Na treatment significantly mitigated the hematopoietic toxicity induced by a sub-lethal radiation dose. Mechanistically, attenuation of ATM-p53 mediated DNA damage response by ON 01210.Na is contributing to the mitigation of radiation-induced hematopoietic toxicity.

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TUNEL staining of bone marrow and spleen sections at 7 d post-radiation. A) Photomicrograph showing TUNEL staining of bone marrow sections at 20× magnification. B) Quantification of TUNEL positive cells in bone marrow sections. *p < 0.01 compared to radiation+vehicle (R+V). C) Photomicrograph showing TUNEL staining of spleen sections at 20× magnification. D) Quantification of TUNEL positive cells in spleen sections. *p < 0.05 compared to radiation+vehicle. Control: no radiation, ON 01210.Na or vehicle; R: 5 Gy radiation; R+V: 5 Gy radiation+vehicle; R+D: 5 Gy radiation+drug (ON 01210.Na).
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Figure 4: TUNEL staining of bone marrow and spleen sections at 7 d post-radiation. A) Photomicrograph showing TUNEL staining of bone marrow sections at 20× magnification. B) Quantification of TUNEL positive cells in bone marrow sections. *p < 0.01 compared to radiation+vehicle (R+V). C) Photomicrograph showing TUNEL staining of spleen sections at 20× magnification. D) Quantification of TUNEL positive cells in spleen sections. *p < 0.05 compared to radiation+vehicle. Control: no radiation, ON 01210.Na or vehicle; R: 5 Gy radiation; R+V: 5 Gy radiation+vehicle; R+D: 5 Gy radiation+drug (ON 01210.Na).

Mentions: TUNEL assay on bone marrow and spleen sections from the ON 01210.Na treated groups showed fewer apoptotic cells than the vehicle treated group (Figure 4A and 4C). Quantification of TUNEL positive cells indicating apoptosis showed significantly lower counts in the ON 01210.Na treated group than the vehicle treated group in both the bone marrow and spleen samples (Figure 4B and 4D; p < 0.01 for bone marrow and p < 0.05 for spleen compared to radiation+vehicle groups).


Administration of ON 01210.Na after exposure to ionizing radiation protects bone marrow cells by attenuating DNA damage response.

Suman S, Maniar M, Fornace AJ, Datta K - Radiat Oncol (2012)

TUNEL staining of bone marrow and spleen sections at 7 d post-radiation. A) Photomicrograph showing TUNEL staining of bone marrow sections at 20× magnification. B) Quantification of TUNEL positive cells in bone marrow sections. *p < 0.01 compared to radiation+vehicle (R+V). C) Photomicrograph showing TUNEL staining of spleen sections at 20× magnification. D) Quantification of TUNEL positive cells in spleen sections. *p < 0.05 compared to radiation+vehicle. Control: no radiation, ON 01210.Na or vehicle; R: 5 Gy radiation; R+V: 5 Gy radiation+vehicle; R+D: 5 Gy radiation+drug (ON 01210.Na).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 4: TUNEL staining of bone marrow and spleen sections at 7 d post-radiation. A) Photomicrograph showing TUNEL staining of bone marrow sections at 20× magnification. B) Quantification of TUNEL positive cells in bone marrow sections. *p < 0.01 compared to radiation+vehicle (R+V). C) Photomicrograph showing TUNEL staining of spleen sections at 20× magnification. D) Quantification of TUNEL positive cells in spleen sections. *p < 0.05 compared to radiation+vehicle. Control: no radiation, ON 01210.Na or vehicle; R: 5 Gy radiation; R+V: 5 Gy radiation+vehicle; R+D: 5 Gy radiation+drug (ON 01210.Na).
Mentions: TUNEL assay on bone marrow and spleen sections from the ON 01210.Na treated groups showed fewer apoptotic cells than the vehicle treated group (Figure 4A and 4C). Quantification of TUNEL positive cells indicating apoptosis showed significantly lower counts in the ON 01210.Na treated group than the vehicle treated group in both the bone marrow and spleen samples (Figure 4B and 4D; p < 0.01 for bone marrow and p < 0.05 for spleen compared to radiation+vehicle groups).

Bottom Line: Post-irradiation treatment of mice with ON 01210.Na also resulted in higher GM-CFU counts.The mitigation effects were accompanied by attenuation of ATM-p53-dependent DNA damage response in the bone marrow cells of ON 01210.Na treated mice.Both phospho-ATM and phospho-p53 were significantly lower in the bone marrow cells of ON 01210.Na treated than in vehicle treated mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular & Cell Biology, Georgetown University Medical Center, Research Building, Room E518, 3970 Reservoir Rd., NW, Washington, DC 20057-1468, USA.

ABSTRACT

Background: Ionizing radiation-induced hematopoietic injury could occur either due to accidental exposure or due to diagnostic and therapeutic interventions. Currently there is no approved drug to mitigate radiation toxicity in hematopoietic cells. This study investigates the potential of ON 01210.Na, a chlorobenzylsulfone derivative, in ameliorating radiation-induced hematopoietic toxicity when administered after exposure to radiation. We also investigate the molecular mechanisms underlying this activity.

Methods: Male C3H/HeN mice (n = 5 mice per group; 6-8 weeks old) were exposed to a sub-lethal dose (5 Gy) of γ radiation using a ¹³⁷Cs source at a dose rate of 0.77 Gy/min. Two doses of ON 01210.Na (500 mg/kg body weight) were administered subcutaneously at 24 h and 36 h after radiation exposure. Mitigation of hematopoietic toxicity by ON 01210.Na was investigated by peripheral white blood cell (WBC) and platelet counts at 3, 7, 21, and 28 d after radiation exposure. Granulocyte macrophage colony forming unit (GM-CFU) assay was done using isolated bone marrow cells, and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) was performed on bone marrow sections at 7 d post-exposure. The DNA damage response pathway involving ataxia telangiectasia mutated (ATM) and p53 was investigated by Western blot in bone marrow cells at 7 d post-exposure.

Results: Compared to the vehicle, ON 01210.Na treated mice showed accelerated recovery of peripheral WBC and platelet counts. Post-irradiation treatment of mice with ON 01210.Na also resulted in higher GM-CFU counts. The mitigation effects were accompanied by attenuation of ATM-p53-dependent DNA damage response in the bone marrow cells of ON 01210.Na treated mice. Both phospho-ATM and phospho-p53 were significantly lower in the bone marrow cells of ON 01210.Na treated than in vehicle treated mice. Furthermore, the Bcl2:Bax ratio was higher in the drug treated mice than the vehicle treated groups.

Conclusions: ON 01210.Na treatment significantly mitigated the hematopoietic toxicity induced by a sub-lethal radiation dose. Mechanistically, attenuation of ATM-p53 mediated DNA damage response by ON 01210.Na is contributing to the mitigation of radiation-induced hematopoietic toxicity.

Show MeSH
Related in: MedlinePlus