Browsing by Subject "Radiosensitization"

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Einfluss eines Glukoseentzugs auf die Strahlenempfindlichkeit von Tumorzellen und Normalzellen
(2018) Ampferl, Rena; Dittmann, Klaus
Radiotherapy is a major pillar of cancer treatment. However, the maximal dose that can be applied to a tumor is limited by side-effects of the irradiated normal tissue. Therefore, to improve treatment success, it is of significant interest to develop new treatment strategies that selectively enhance the cytotoxic effect of radiation in tumor cells while sparing healthy tissue. For this purpose, it is necessary to exploit differences between tumor cells and normal cells. Thus, tumor cells are characterized by metabolizing glucose preferentially to lactate regardless of the availability of oxygen (Warburg effect, aerobic glycolysis), while normal cells oxidize most of the glucose in the mitochondria if oxygen is present. Because the Warburg effect only produces low amounts of ATP per molecule of glucose when compared to mitochondrial glucose oxidation, tumor cells rely on high glucose supply. Hence, it was the aim of this study to investigate whether a glucose starvation during radiotherapy, which requires energy-dependent repair of DNA damage, is an appropriate strategy to selectively enhance radiosensitivity of tumor cells, but not of normal cells. It was shown that glucose starvation inhibited proliferation of the tumor cell lines A549 and FaDu, but not that of the normal fibroblasts HSF7. Moreover, deprivation of glucose induced cell death selectively in tumor cells, which occurred mainly via necrosis. Combining glucose starvation with radiotherapy led to selective radiosensitization of both tumor cell lines, which was accompanied by impaired repair of radiation-induced DNA double-strand breaks (DNA DSBs). In this context, it turned out that in tumor cells glucose is essential for the late stage of DNA DSB repair starting from 13 h after irradiation. Furthermore, an inhibition of radiation-induced histone acetylation as well as KAP1 phosphorylation could be observed in tumor cells following glucose starvation, indicating an impairment of radiation-induced chromatin relaxation. Because opening of the chromatin structure is particularly important for the repair of DNA DSBs within heterochromatin and because these DSBs are the ones that are repaired at late time points after irradiation, it can be assumed that in tumor cells glucose starvation mainly impairs the repair of heterochromatic DNA DSBs. Further investigations revealed that in tumor cells glucose starvation does not cause lack of nuclear acetyl-CoA, which is the substrate for the acetylation of histones, and therefore this could be excluded as cause of the observed inhibition of histone acetylation. However, it is known that the histone deacetylase Sirt1 is activated in response to glucose starvation. Histone deacetylation by Sirt1 could counteract radiation-induced histone acetylation, thus impairing chromatin relaxation as well as repair of DNA DSBs after irradiation. In fact, it was shown that inhibition of Sirt1 by sirtinol can partly abrogate the impaired repair of radiation-induced DNA DSBs that was observed in tumor cells under glucose-free conditions. However, the inhibitory effect of glucose starvation on DNA DSB repair in tumor cells could not only be observed under glucose-free conditions. Thus, reducing the glucose concentration to 0.5 g/l was enough to impair DSB repair following irradiation to the same degree as after total deprivation of glucose. Furthermore, it turned out that under glucose-free conditions DNA DSB repair in tumor cells was promoted by autophagy already after irradiation with 2 Gy. Finally, it was shown that, in addition to DNA DSB repair, also tumor metabolism is influenced by glucose starvation. Thus, deprivation of glucose impaired the radiation-induced switch of glucose metabolism that was characterized by increased aerobic glycolysis and decreased mitochondrial glucose oxidation, and this can also contribute to radiosensitization of the cells. In contrast to tumor cells, glucose starvation neither caused radiosensitization nor impaired the repair of radiation-induced DNA DSBs in normal fibroblasts. Moreover, in these cells, glucose starvation had no influence on histone acetylation and KAP1 phosphorylation after irradiation. These results demonstrate that glucose starvation is an appropriate in vitro strategy to selectively sensitize tumor cells to radiotherapy without influencing the radiosensitivity of normal cells.