Glycerol restores p53-dependent radiosensitivity of human head and neck cancer cells bearing mutant p53

Mutation or inactivation of p53 is known to be present in approximately 50% of human cancers. We propose here a novel strategy for overcoming this pro blem in mutant p53-targeting cancer therapies. We examined the restoration of radiation-induced p53-dependent apoptosis by a chemical chaperone (glyce rol) in human head and neck cancer cells (SAS cells, showing wild-type p53 phenotype). SAS cells transfected with mutant p53 (SAS/mp53) showed radiore sistance compared with SAS cells (SAS/neo) transfected with neo vector as a control, but became radiosensitive when pre-treated with glycerol before X -ray irradiation. Apoptosis in the SAS/mp53 cells was induced by X-rays wit h glycerol pre-treatment. but not without glycerol pre-treatment, whereas a poptosis in the SAS/neo cells was induced in both cases. Gel mobility-shift assays showed that after X-ray irradiation combined with glycerol pre-trea tment, mp53 was able to bind to the sequence-specific region upstream of th e bax gene regulating apoptosis. These results suggest that glycerol is eff ective in inducing a conformational change of p53 and restoring normal func tion to mp53, leading to enhanced radiosensitivity through the induction of apoptosis. This novel tool for enhancement of radiosensitivity in cancer c ells bearing mp53 may be useful for p53-targeted radiotherapy. (C) 2000 Can cer Research Campaign.