Restoration of p53 to limit tumor growth.
OBJECTIVE
p53 mutation occurs in over half of all human tumors. Among the remaining tumors, although they may process a wild-type p53, the pathways of p53-induced cell-cycle arrest and apoptosis are deficient. Therefore, p53 serves as a unique molecular target for cancer therapy. This review focuses on the current progress regarding restoration of p53 function in human tumors for molecularly targeted therapy.


RESULTS
Targeting p53 for cancer therapy has been intensively pursued. CP-31398 was the first small molecule identified with the ability to restore the wild-type conformation to mutant p53. Subsequently, PRIMA-1 and ellipticine were found to be able to induce mutant p53-dependent cell death. Nutlin was developed to rescue wild-type p53 from degradation mediated by MDM2. More recently, p53 family members can be activated and therefore serve as substitutes of p53 in tumor cells and induce cell death.


CONCLUSIONS
Loss of p53 function is a characteristic of almost all human tumors. Recent advances demonstrate that reconstitution of p53 function is possible and practical as a promising antitumor strategy.
Wang
Wenge
W
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
El-Deiry
Wafik S
WS
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001372:Aza Compounds / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle; D004611:Ellipticines / Q000494:pharmacology / Q000627:therapeutic use; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004611:Ellipticines; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C482203:nutlin 1; C034192:ellipticine; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one; C402665:CP 31398