Conclusion
The combination of the radioprotectors PT and SIL with the radiomitigators NR and FSL1 confer effective, long-term protection against γ radiation in vivo. This strategy is potentially capable of protecting mammals against ionizing radiations.
Methods
Plant-derived polyphenols were screened for their potential ability to confer radioprotection to mice given a lethal whole-body γ radiation (137Cs) dose expected to kill 50% of the animals in 30 days. Telomere and centromere staining, Q-FISH and comet assays were used to investigate chromosomal aberration, micronuclei formation and DNA breaks. Molecular oxidations were investigated by enzyme immunoassays and UPLC-MS/MS. RT-PCR, western blotting and siRNA-induced gene silencing were used to study signaling mechanisms and molecular interactions.
Objective
To investigate if combinations of natural polyphenols, known for their antioxidant potential, could protect against ionizing radiations.
Results
The combination of pterostilbene (PT) and silibinin (SIL) was the most effective against γ-irradiation, resulting in 100% of the mice surviving at 30 days and 20% survival at one year. Treatment post γ-irradiation with two potential radiomitigators nicotinamide riboside (NR, a vitamin B3 derivative), and/or fibroblast-stimulating lipoprotein 1 (FSL1, a toll-like receptor 2/6 agonist), did not extend survival. However, the combination of PT, SIL, NR and FSL1 achieved a 90% survival one year post γ-irradiation. The mechanism involves induction of the Nrf2-dependent cellular antioxidant defense, reduction of NF-kB signaling, upregulation of the PGC-1α/sirtuins 1 and 3 axis, PARP1-dependent DNA repair, and stimulation of hematopoietic cell recovery. The pathway linking Nrf2, sirtuin 3 and SOD2 is key to radioprotection. Importantly, this combination did not interfere with X-ray mediated killing of different tumor cells in vivo.