Prospective therapeutic applications of p53 inhibitors.
p53, in addition to being a key cancer preventive factor, is also a determinant of cancer treatment side effects causing excessive apoptotic death in several normal tissues during cancer therapy. p53 inhibitory strategy has been suggested to protect normal tissues from chemo- and radiotherapy, and to treat other pathologies associated with stress-mediated activation of p53. This strategy was validated by isolation and testing of small molecule p53 inhibitor pifithrin-alpha that demonstrated broad tissue protecting capacity. However, in some normal tissues and tumors p53 plays protective role by inducing growth arrest and preventing cells from premature entrance into mitosis and death from mitotic catastrophe. Inhibition of this function of p53 can sensitize tumor cells to chemo- and radiotherapy, thus opening new potential application of p53 inhibitors and justifying the need in pharmacological agents targeting specifically either pro-apoptotic or growth arrest functions of p53.
Gudkov
Andrei V
AV
Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. gudkov@ccf.org
Komarova
Elena A
EA
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles; D004357:Drug Synergism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011837:Radiation-Protective Agents / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use; D014050:Toluene / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D018696:Neuroprotective Agents; D011837:Radiation-Protective Agents; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin