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Abstract 1390: A combination of natural polyphenols, a NAD+booster, and a Toll-like receptor 2/6 agonist exerts high radioprotection in normal tissues without interfering with the anticancer efficacy of ionizing radiations

Ionizing radiation damages cells via direct ionization of DNA and other cellular targets as well as by indirect effects through reactive oxygen species. The response to radiation exposure depends on the cell type and dose of radiation, inherent tissue sensitivity and repair, and modulating intracellular factors that include cell cycle status, O2 pressure, and levels of thiols and other antioxidants. Potentially protective agents against exposure to harmful radiation have been investigated for decades. However, no ideal radioprotector is currently available. A wide range of phytochemicals are antioxidants and, thus, potentially radioprotective. Topical administration of Pterostilbene (3,5-dimethoxy-49-hydroxystilbene, PTER, a natural stilbene originally isolated from the heartwood of red sandalwood) protects against chronic UVB radiation-induced skin carcinogenesis, and protects the skin against the burning and irritation effects of acute UVB doses. The protection elicited by PTER is not due to physico-chemical screen or direct antioxidant effects. PTER induces an increase in our overall physiological antioxidant defences. Thus, it is plausible that PTER, could also exert protection against other types of ionizing radiation. We investigated the effect of PTER against ionizing radiation and found that the combination of PTER and silibinin [SIL, (2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydrochromen-4-one, a natural flavanone isolated from the silybum marianum (milk thistle)] exerts radioprotection against γ radiation injury under in vivo conditions. NAD+ is an essential coenzyme in ATP production, and NAD+ consuming enzymes like poly(ADP-ribose) polymerases and sirtuins are important regulators in chromatin-restructuring processes during repair and epigenetics/transcriptional adaption. Nicotinamide, an NAD+ precursor, has been shown to improve the post-radiation repair capacity in cells in a concentration-dependent manner. Hence, NAD+ precursors could function as potential radiomitigators in vivo. Furthermore, replenishment of hematopoietic sites is critical for recovery following radiation exposure. Interestingly, a recent report shows that the Toll-like receptor (TLR) 2/6 agonist, FSL (fibroblast-stimulating lipopeptide)-1 (FSL-1), therapeutically mitigates acute radiation syndrome. We found the combination of PTER, SIL, nicotinamide riboside (a NAD+ precursor) and FSL-1 favoured the long-term survival of irradiated mice. Moreover, this radioprotecting/radiomitigating combination did not reduce the anticancer efficacy of X rays in growing human A549 (lung adenocarcinoma) and MDA-MB-231 (triple negative mammary carcinoma) xenografts. Citation Format: Elena Obrador, Rosario Salvador, Rafael Lopez-Blanch, Ali Jihad-Jebbar, Jose I. Villaescusa, Alegria Montoro, Ryan W. Dellinger, Jose M. Estrela. A combination of natural polyphenols, a NAD+ booster, and a Toll-like receptor 2/6 agonist exerts high radioprotection in normal tissues without interfering with the anticancer efficacy of ionizing radiations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1390.