title: A small molecule inhibitor of p53 stimulates amplification of hematopoietic stem cells but does not promote tumor development in mice.
abstract: 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.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Katerina I
authors.initials: KI
authors.lastname: Leonova
authors.forename: Jelena
authors.initials: J
authors.lastname: Shneyder
authors.forename: Marina P
authors.initials: MP
authors.lastname: Antoch
authors.forename: Illia A
authors.initials: IA
authors.lastname: Toshkov
authors.forename: Liliya R
authors.initials: LR
authors.lastname: Novototskaya
authors.forename: Pavel G
authors.initials: PG
authors.lastname: Komarov
authors.forename: Elena A
authors.initials: EA
authors.lastname: Komarova
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
mesh_terms: 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*
chemical_list: D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin
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