Pifithrin-α as a potential cytoprotective agent in radiotherapy: Protection of normal tissue without decreasing therapeutic efficacy in glioma cells

摘要

Activation of p53 has been causally linked to normal tissue damage after irradiation. Pifithrin-(PFT-), a specific inhibitor of p53, has been suggested as a combinatory agent in the treatment of p53-deficient tumors in which inhibition of p53 would not compromise therapeutic efficacy but would decrease p53-mediated side effects in normal tissue. We tested this concept for radiotherapy of p53-deficient and-proficient glioma. We observed significant interaction of PFT-with radiation-induced G1 checkpoint activation and plating efficiency only in glioma cells expressing at least one wild-type allele of p53. This interaction was correlated with PFT-mediated inhibition of radiation-induced expression of the p53 target gene p21~(Waf1). Despite inhibition of p53 function we did not observe significant changes in radiosensitivity after treatment with PFT-in either p53-deficient or p53-proficient tumor cells. We confirmed these results in p53-proficient lung cancer cells. In contrast, PFT-significantly increased the fraction of normal astrocytes and fibroblasts surviving irradiation; this was accompanied by improved DNA damage repair, speaking against an accumulation of cells with genetic lesions after PFT-treatment. In conclusion, PFT-might prove useful in protecting normal tissue from the side effects of radiotherapy without reducing the efficacy of treatment for both p53-proficient and-deficient tumors.