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Suppression of p53: a new approach to overcome side effects of antitumor therapy
1Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Abstract:
The p53 protein is traditionally believed to be a tumor suppressor. Activation of p53-dependent apoptosis in response to damage to cell DNA provides for the elimination of possible tumor cell precursors. However, in some cases the activity of p53 can be dangerous for the organism. Thus, p53-dependent apoptosis induced in normal tissues during chemo- and radiotherapy can cause severe side effects of antitumor therapy and, therefore, limits its efficiency. This review analyzes experimental data on the role of p53 in the primary and late tissue response to DNA-damaging exposures. Comparison of normal and p53-deficient mice indicated that the apoptosis in radiosensitive tissues during the first hours after irradiation is really caused by the activity of p53 which, in turn, is determined by a high level of expression of mRNA of p53. We supposed that a temporary suppression of p53 can decrease the damage to sensitive tissues and accelerate their recovery after the antitumor radio- and chemotherapy. To test this hypothesis, we have isolated a chemical inhibitor of p53 and determined its activity in vitro and in vivo. This compound, called pifithrin-alpha, protects wild-type mice against lethal doses of radiation, has no effect on p53-deficient animals, and does not induce visible tumors. These results show that the suppression of p53 is a promising approach in the prevention of side effects of antitumor therapy.
Insights
Suppressing p53 activity, a protein traditionally viewed as a tumor suppressor, can protect normal tissues from damage during cancer therapy. This approach shows promise in reducing side effects and improving treatment outcomes.
Area of Science:
- Molecular Biology
- Oncology
- Radiotherapy
Background:
- The p53 protein is a key regulator of apoptosis, crucial for eliminating damaged cells.
- While beneficial for tumor suppression, p53 activation in normal tissues can lead to severe side effects during cancer therapy, limiting treatment efficacy.
Purpose of the Study:
- To investigate the role of p53 in tissue response to DNA-damaging agents.
- To evaluate the potential of transient p53 suppression to mitigate therapy-induced side effects.
Main Methods:
- Comparative analysis of normal and p53-deficient mice following DNA-damaging exposures.
- In vitro and in vivo assessment of a novel p53 inhibitor, pifithrin-alpha.
Main Results:
- p53 activity directly correlates with apoptosis in radiosensitive tissues post-irradiation.
- Pifithrin-alpha demonstrated radioprotective effects in wild-type mice but not in p53-deficient animals.
- The inhibitor did not induce observable tumor formation.
Conclusions:
- Transient suppression of p53 activity is a viable strategy to prevent side effects of chemo- and radiotherapy.
- Pifithrin-alpha shows potential as a therapeutic agent for protecting normal tissues during cancer treatment.