Chemoprotection from p53-dependent apoptosis: potential clinical applications of the p53 inhibitors

The p53 tumor suppressor pathway is a key mediator of stress response that protects the organism from accumulating genetically altered and potentially cancerous cells by inducing growth arrest or apoptosis in damaged cells. H owever, under certain stressful conditions, p53 activity can result in mass ive apoptosis in sensitive tissues, leading to severe pathological conseque nces for the organism. One such situation is anticancer therapy that is oft en associated with general genotoxic stress, leading to p53-dependent apopt osis in the epithelia of the digestive tract and in the hematopoietic syste m. A chemical inhibitor of p53, capable of suppressing p53-mediated apoptos is, was shown to protect mice from lethal doses of gamma-radiation, making pharmacological suppression of p53 a perspective therapeutic approach to re duce the side-effects of cancer treatment. There are other situations, besi des anti-cancer therapy, when humans are exposed to stressful conditions kn own to involve p53 activation, which, in extreme cases, could result in the development of life-threatening diseases. Here we review the experimental evidence on the role of p53 in tissue injuries associated with hypoxia (hea rt and brain ischemias) and hyperthermia (fever and bums), comparing these pathologies with the consequences of genotoxic stress of cancer treatment. The accumulated information points to the involvement of p53 in the generat ion of the pathological outcome of the above stresses, making them potentia l targets for the therapeutic application of p53 inhibitors. (C) 2001 Elsev ier Science Inc. All rights reserved.