RESUMO
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.
Assuntos
Benzotiazóis/farmacologia , Células-Tronco Hematopoéticas/citologia , Neoplasias/patologia , Tolueno/análogos & derivados , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Raios gama , Células-Tronco Hematopoéticas/efeitos dos fármacos , Camundongos , Camundongos Knockout , Neoplasias/metabolismo , Tolueno/farmacologiaRESUMO
Retinoic acid (RA) displays potent anticarcinogenic activities that are mediated by the nuclear retinoic acid receptors (RARs). However, use of RA in oncology is limited by RA resistance acquired during carcinogenesis. Moreover, in some cancers, RA facilitates rather than inhibits growth. A clue to this paradoxical behavior was recently suggested by the findings that RA also activates PPARbeta/delta, a receptor involved in mitogenic and anti-apoptotic activities. The observations that partitioning of RA between its two receptors is regulated by two intracellular lipid-binding proteins-CRABP-II, which targets RA to RAR, and FABP5, which delivers it to PPARbeta/delta-further suggest that RA resistance may stem from the deregulation of the binding proteins, resulting in activation of PPARbeta/delta rather than RAR. Here, we show that, in the RA-resistant mouse model of breast cancer MMTV-neu, RA indeed activates the nonclassical RA receptor PPARbeta/delta. This behavior was traced to an aberrantly high intratumor FABP5/CRABP-II ratio. Decreasing this ratio in mammary tissue diverted RA from PPARbeta/delta to RAR and suppressed tumor growth. The data demonstrate the existence of a mechanism that underlies RA resistance in tumors, indicate that CRABP-II functions as a tumor suppressor, and suggest that the inhibition of FABP5 may comprise a therapeutic strategy for overcoming RA resistance in some tumors.
Assuntos
Antineoplásicos/farmacologia , Carcinoma/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Ligação a Ácido Graxo/metabolismo , Neoplasias Mamárias Animais/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores do Ácido Retinoico/agonistas , Tretinoína/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/antagonistas & inibidores , PPAR delta/agonistas , PPAR beta/agonistas , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
The mammalian circadian system has been implicated in the regulation of various biological processes including those involved in genotoxic stress responses and tumor suppression. Here we report that mice with the functional deficiency in circadian transcription factor CLOCK (Clock/Clock mutant mice) do not display predisposition to tumor formation both during their normal lifespan or when challenged by gamma- radiation. This phenotype is consistent with high apoptotic and low proliferation rate in lymphoid tissues of Clock mutant mice and is supported by the gene expression profiling of a number of apoptosis and cell cycle-related genes, as well as by growth inhibition of cells with CLOCK downregulation. At the same time, Clock mutant mice respond to low-dose irradiation by accelerating their aging program, and develop phenotypes that are reminiscent of those in Bmal1-deficient mice. Taken together, our results demonstrate the dichotomy in biological consequences of the disruption of the circadian clock with respect to ageing and cancer. They also highlight the existence of a complex interconnection between ageing, carcinogenesis and individual components of the circadian clock machinery.
Assuntos
Envelhecimento/genética , Transformação Celular Neoplásica/genética , Transtornos Cronobiológicos/genética , Ritmo Circadiano/genética , Mutação/genética , Transativadores/genética , Envelhecimento/metabolismo , Envelhecimento/efeitos da radiação , Senilidade Prematura/genética , Senilidade Prematura/metabolismo , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Proteínas CLOCK , Proliferação de Células/efeitos da radiação , Transformação Celular Neoplásica/metabolismo , Transtornos Cronobiológicos/metabolismo , Transtornos Cronobiológicos/fisiopatologia , Regulação para Baixo/genética , Regulação para Baixo/efeitos da radiação , Feminino , Raios gama/efeitos adversos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Predisposição Genética para Doença/genética , Imunidade Inata/genética , Imunidade Inata/efeitos da radiação , Tecido Linfoide/metabolismo , Tecido Linfoide/efeitos da radiação , Masculino , Camundongos , FenótipoRESUMO
In a small controlled study, clevudine, a potent inhibitor of hepadnaviruses, including hepatitis B virus and woodchuck hepatitis virus, suppressed hepatitis delta virus (HDV) viremia in chronically infected woodchucks. Suppression was correlated with the marked reduction of woodchuck hepatitis virus surface antigen in individual animals, consistent with the concept that repression of surface antigen expression may be a useful antiviral strategy for HDV.