Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation.
p53-dependent apoptosis contributes to the side effects of cancer treatment, and genetic or pharmacological inhibition of p53 function can increase normal tissue resistance to genotoxic stress. It has recently been shown that p53 can induce apoptosis through a mechanism that does not depend on transactivation but instead involves translocation of p53 to mitochondria. To determine the impact of this p53 activity on normal tissue radiosensitivity, we isolated a small molecule named pifithrin-mu (PFTmu, 1) that inhibits p53 binding to mitochondria by reducing its affinity to antiapoptotic proteins Bcl-xL and Bcl-2 but has no effect on p53-dependent transactivation. PFTmu has a high specificity for p53 and does not protect cells from apoptosis induced by overexpression of proapoptotic protein Bax or by treatment with dexamethasone (2). PFTmu rescues primary mouse thymocytes from p53-mediated apoptosis caused by radiation and protects mice from doses of radiation that cause lethal hematopoietic syndrome. These results indicate that selective inhibition of the mitochondrial branch of the p53 pathway is sufficient for radioprotection in vivo.
Strom
Evguenia
E
Cleveland BioLabs, Inc., 11000 Cedar Ave., Cleveland, Ohio 44106, USA.
Sathe
Swati
S
Komarov
Pavel G
PG
Chernova
Olga B
OB
Pavlovska
Ivanda
I
Shyshynova
Inna
I
Bosykh
Dmitry A
DA
Burdelya
Lyudmila G
LG
Macklis
Roger M
RM
Skaliter
Rami
R
Komarova
Elena A
EA
Gudkov
Andrei V
AV
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D052160:Benzothiazoles; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014050:Toluene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
D051017:Apoptosis Regulatory Proteins; D052160:Benzothiazoles; D011837:Radiation-Protective Agents; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D003907:Dexamethasone; C121565:pifithrin