A small molecule inhibitor of p53 stimulates amplification of hematopoietic stem cells but does not promote tumor development in mice.
It has been shown that genetic inhibition of p53 leads to enhanced proliferation of hematopoietic stem cells (HSCs). This could, in theory, contribute to the increased frequency of tumor development observed in p53-deficient mice and humans. In our previous work, we identified chemical p53 inhibitors (PFTs) that suppress the transactivation function of p53 and protect cultured cells and mice from death induced by gamma irradiation (IR). Here we found that when applied to bone marrow cells in vitro or injected into mice, PFTb impeded IR-induced reduction of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) population sizes. In addition, we showed that PFTb stimulated HSC and HPC proliferation in the absence of IR in vitro and in vivo and mobilized HSCs to the peripheral blood. Importantly, however, PFTb treatment did not affect the timing or frequency of tumor development in irradiated p53 heterozygous mice used as a model for determination of carcinogenicity. Thus, although PFTb administration led to increased numbers of HSCs and HPCs, it was not carcinogenic in mice. These findings suggest that chemical p53 inhibitors may be clinically useful as safe and effective stimulators of hematopoiesis.
Leonova
Katerina I
KI
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Shneyder
Jelena
J
Antoch
Marina P
MP
Toshkov
Illia A
IA
Novototskaya
Liliya R
LR
Komarov
Pavel G
PG
Komarova
Elena A
EA
Gudkov
Andrei V
AV
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005720:Gamma Rays; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin
Nature. 1992 Mar 19;356(6366):215-21
1552940
Curr Pharm Des. 2002;8(5):379-94
12069376
Nature. 2009 Aug 27;460(7259):1140-4
19668186
Nat Genet. 1994 Sep;8(1):66-9
7987394
J Exp Med. 1996 Apr 1;183(4):1797-806
8666936
Nature. 2008 May 8;453(7192):228-32
18418377
Nature. 2009 Aug 27;460(7259):1085-6
19713919
Blood. 1993 Dec 1;82(11):3327-32
8241503
Cell. 2004 Jul 23;118(2):149-61
15260986
Blood. 2006 Jan 1;107(1):358-66
16150936
Nature. 2006 Sep 14;443(7108):214-7
16957739
Science. 1999 Sep 10;285(5434):1733-7
10481009
Nature. 2009 Aug 27;460(7259):1149-53
19668189
Toxicol Pathol. 2001;29 Suppl:24-9
11695559
J Immunol. 1988 Dec 1;141(11):3697-707
2460547
Nature. 2004 Nov 18;432(7015):307-15
15549092
Proc Natl Acad Sci U S A. 1989 Jun;86(12):4634-8
2660142
Oncogene. 2004 Apr 22;23(19):3265-71
15064735
Nature. 2009 Aug 27;460(7259):1145-8
19668190
Exp Hematol. 2003 Jun;31(6):521-7
12829028
Biochem Biophys Res Commun. 2005 Jun 10;331(3):726-36
15865929
Nature. 1991 Jun 6;351(6326):453-6
2046748
Cell Stem Cell. 2009 Jan 9;4(1):37-48
19128791
Science. 1996 Jul 12;273(5272):242-5
8662508
Semin Cancer Biol. 1998;8(5):389-400
10101804
Nature. 2009 Aug 27;460(7259):1132-5
19668191
Nature. 2009 Aug 27;460(7259):1136-9
19668188
Radiat Res. 2003 Mar;159(3):320-7
12600234
Cancer Res. 1997 Aug 1;57(15):3245-52
9242456
Development. 2006 Jan;133(2):363-9
16368933
Exp Hematol. 2008 Oct;36(10):1236-43
18562080
Blood. 2007 Feb 15;109(4):1736-42
17032926
Curr Biol. 1994 Jan 1;4(1):1-7
7922305