Protective Effects of p53 Regulatory Agents Against High-LET Radiation-Induced Injury in Mice

Abstract

Radiation damage to normal tissues is one of the most serious concerns in radiation therapy, and the tolerance dose of the normal tissues limits the therapeutic dose to the patients. p53 is well known as a transcription factor closely associated with radiation-induced cell death. We recently demonstrated the protective effects of several p53 regulatory agents against low-LET X- or γ-ray-induced damage. Although it was reported that high-LET heavy ion radiation (>85 keV/μm) could cause p53-independent cell death in some cancer cell lines, whether there is any radioprotective effect of the p53 regulatory agents against the high-LET radiation injury in vivo is still unclear. In the present study, we verified the efficacy of these agents on bone marrow and intestinal damages induced by high-LET heavy-ion irradiation in mice. We used a carbon-beam (14 keV/μm) that was shown to induce a p53-dependent effect and an iron-beam (189 keV/μm) that was shown to induce a p53-independent effect in a previous study. Vanadate significantly improved 60-day survival rate in mice treated with total-body carbon-ion (p < 0.0001) or iron-ion (p < 0.05) irradiation, indicating its effective protection of the hematopoietic system from radiation injury after high-LET irradiation over 85 keV/μm. 5CHQ also significantly increased the survival rate after abdominal carbon-ion (p < 0.02), but not iron-ion irradiation, suggesting the moderate relief of the intestinal damage. These results demonstrated the effectiveness of p53 regulators on acute radiation syndrome induced by high-LET radiation.

APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy

“…This observation is in contrast to previous reports implicating that mutant p53 is conferring radio-resistance in various cancer types when tested with low-LET type of irradiation [58,59]. The presence of mutant p53 has been associated with impaired DNA damage response, compromised cell cycle checkpoints collectively contributing to the decreased sensitivity to RT [29,60,61]. Our findings suggest that in high-LET alpha particle-based RT, tumors harboring mutant p53 are profoundly affected and that reactivation of the WT form in such tumors could be instrumental in augmenting the effect of the RT even further.…”

Enhanced Effects of Chronic Restraint-Induced Psychological Stress on Total Body Fe-Irradiation-Induced Hematopoietic Toxicity in Trp53-Heterozygous Mice

“…For hematopoietic system, exquisite regulation of Trp53 activity is critical for maintaining homeostasis under normal and stress conditions, and loss of Trp53 function could promote leukemia and lymphoma development in humans and mice [71]. In contrast to Trp53-independent apoptosis induced by high-LET IR in cultured cells in vitro [72], cell death in vivo induced by high-LET radiation is at least partially Trp53-dependent [73]. IR-induced hematopoietic stem cell apoptosis is via the Trp53-Puma pathway [74].…”

p53 Modulates Radiosensitivity in Head and Neck Cancers—From Classic to Future Horizons

“…The p53 regulatory agents have been shown to be effective in the protection against acute irradiation syndrome when high-LET heavy ion radiation (> 85 keV/μm) has been used [ 44 ].…”