Restoration of wild‐type p53 function in human cancer: Relevance for tumor therapy

Abstract

In the majority of human cancers, the tumor suppressor activity of p53 is impaired because of mutational events or interactions with other proteins (ie, MDM2). The loss of p53 function is responsible for increased aggressiveness of cancers, while tumor chemoresistance and radioresistance are dependent upon the expression of mutant p53 proteins. Review of the literature indicates that p53 acts primarily as a transcription factor whose function is subject to a complex and diverse array of covalent post-translational modifications that markedly influence the expression of p53 target genes responsible for cellular responses such as growth arrest, senescence, or apoptosis. The ability of p53 to induce apoptosis in cancer cells is believed essential for cancer therapy. Numerous data indicate that p53 dependent apoptosis is a relevant factor in determining the efficacy of anticancer treatments. Thus, the development of new strategies for restoration of p53 function in human tumors is considered an important issue. Two main approaches for restoration of p53 function have been pursued that impact anticancer treatments: (a) de novo expression of wild-type p53 (wt-p53) through gene therapy and (b) identification of small molecules reactivating wt-p53 function. The extensive body of knowledge acquired has identified manipulations of p53 signaling as a relevant issue for successful therapies. In this context, the recognition of p53 status in cancer cells is significant and would help considerably in the selection of an appropriate therapeutic approach. p53 manipulations for cancer therapy have revealed the need for specificity of p53 activation and ability to spare body tissues. Furthermore, the promising results obtained by using molecules competent to reactivate wt-p53 functions in cancer cells provide the basis for the design of new molecules with lower side effects and higher anti-tumor efficiency. The reexpression and reactivation of p53 protein in human cancer cells would increase tumor susceptibility to radiation or chemotherapy enhancing the efficacy of standard therapeutic protocols.