Starvation-dependent differential stress resistance: a new frontier for radiotherapy?

Since its discovery in the 19th century, radiotherapy has been one of the major medical treatments in oncology, providing curative, adjuvant and palliative therapy and improving overall survival. However, a low dose of irradiation (IR) is delivered outside the tumor target volume, increasing side effects and modifying the interaction between cancer and surrounding stromal cells. Recently, the role of fasting or short term starvation (STS) for cancer patients receiving chemotherapy has been taken into account to enhance therapeutic index and to prevent side effects, but no data are available from patients receiving radiotherapy. Here we investigated in vitro the effect of STS on the efficacy of radiotherapy in tumor cell lines derived from primary and metastatic site, and in normal cell lines. Cells were incubated in low glucose (0.5gr/l + 1%FBS) (STS condition) or normal glucose ( 1gr/l + 10 %FBS) DMEM medium for 24 hours and treated with a single dose of 5Gyx1 ( normal fibroblasts and adenocarcinoma cells), 10Gyx1 (metastatic prostate cell line) and 8Gyx1 (metastatic pancreatic cell line). For the irradiation experiments, the flasks containing the cells were placed in a plexiglass custom-built phantom developed to mimic the passage of radiation through human tissue. The levels of DNA damage were evaluated using alkaline comet assay. The results indicated that after STS the radiation dose significantly increased levels of DNA damage in metastatic cancer cell lines but not in normal cells, compared to baseline values. Furthermore, using clonogenic assay, we observed that STS had a significative radiosensitizing effect on metastatic cell lines, reducing significantly the surviving fraction. Conversely, such radiosensitizing effect was not observed in fibroblastic cells. Moreover, our in vitro results indicate that adenocarcinoma patients could not take advantage of short-term starvation before radiotherapy. In conclusion, our results suggest that changings in cancer metabolism due to starvation could enhance the efficacy of radiotherapy treatment in in vitro metastatic cancer cells without impact on survival fraction of healthy cells.