Abstract 3043: Survivin-mediated radio-sensitization response in p53 mutant tumor cells

Abstract

Abstract Doses of ionizing radiation ≤100 mGy induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to doses as low as 5 mGy. Experiments were performed using two murine sarcomas, SA-NH and FSa,grown either in culture or as tumors, and two human cancer cell lines, Panc-1 (pancreatic epithelioid carcinoma) and MDA-MB-231 (breast adenocarcinoma). Doses of 5 mGy were used to induce changes in the response of these tumor cells to higher therapy doses using a multi-dosing paradigm. Effects on radiation sensitivity were associated with changes in both survivin concentration and its translocation to the cytoplasm (SA-NH, p53 wild type) or nucleus (FSa, Panc-1 and MDA-MB-231, p53 mutant). In vitro survival assays (2 Gy per fraction, two once daily fractions) and tumor growth delay (TGD) (5 Gy per fraction, five once daily fractions) studies were performed on SA-NH and FSa cells. Intracellular localization of survivin was determined by ELISA and correlated to survival response. 2 Gy alone had no effect on intracellular translocation of survivin. When preceded 15 min earlier by a 5 mGy exposure, survivin increased in the cytoplasm of SA-NH as compared to the nuclei of FSa, Panc-1 and MDA-MB-231 cells. SA-NH tumors were protected by 5 mGy exposures (1.9 day decrease in TGD, P = 0.032) while FSa tumors were sensitized (4.5 day increase in TGD, P < 0.001). Panc-1 and MDA-MB-231 tumor cells were also sensitized to ionizing radiation following 5 mGy exposures. Exposure of SA-NH to 4 mM of the free radical scavenger N-acetylcysteine inhibited the effect of 5 mGy on inducing this adaptive response. We have identified a very low radiation dose-induced survivin-mediated radio-sensitization response that could enhance therapeutic outcomes associated with the increased usage of imaging procedures in radiation therapy. This work was supported by NIH/NCI grant R01 CA132998 and DOE Low Dose Program/Project Grant DE-SC0001271 (D.J.G.) Citation Format: David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Ralph R. Weichselbaum, Alfred W. Rademaker, Gayle E. Woloschak, Jian Jian Li. Survivin-mediated radio-sensitization response in p53 mutant tumor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3043.