Assuntos
Epigênese Genética/efeitos dos fármacos , Leucemia de Células T/tratamento farmacológico , Panobinostat/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptor Notch1/genética , Linfócitos T/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Epigênese Genética/genética , Epigenômica/métodos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Leucemia de Células T/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transcrição Gênica/genéticaRESUMO
Inhibitor of apoptosis proteins (IAPs) antagonize caspase activation and regulate death receptor signaling cascades. LCL-161 is a small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway, enhanced TNF production and sensitization to apoptosis mediated by the extrinsic pathway. SMAC mimetics are undergoing clinical evaluation in a range of hematological malignancies. Burkitt-like lymphomas are hallmarked by a low apoptotic threshold, conveying sensitivity to a range of apoptosis-inducing stimuli. While evaluating LCL-161 in the Eµ-Myc model of aggressive Burkitt-like lymphoma, we noted unexpected resistance to apoptosis induction despite 'on-target' IAP degradation and NFκB activation. Moreover, LCL-161 treatment of lymphoma-bearing mice resulted in apparent disease acceleration concurrent to augmented inflammatory cytokine-release in the same animals. Indiscriminate exposure of lymphoma patients to SMAC mimetics may therefore be detrimental due to both unanticipated prolymphoma effects and increased susceptibility to endotoxic shock.
Assuntos
Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Linfoma de Células B/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Compostos de Piridínio/farmacologia , Animais , Células Cultivadas , Óxidos N-Cíclicos , Quinase 9 Dependente de Ciclina/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Indolizinas , Linfoma de Células B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismoRESUMO
Following the establishment of histone deacetylases (HDACs) as promising therapeutic targets for the reversal of aberrant epigenetic states associated with cancer, the development of HDAC inhibitors (HDACi) and their underlying mechanisms of action has been a significant area of scientific interest. HDACi induce diverse biological responses including the inhibition of cell proliferation by blocking progression through the G1 or G2/M phases of the cell cycle. As a putative tumor-suppressor protein, p21(waf1/cip1) influences cell proliferation by inhibiting the activity of cyclin-cyclin-dependent kinase (CDK) complexes at the G1/S and G2/M cell cycle checkpoints. HDACi transcriptionally activate CDKN1A, and it has been proposed that induction of p21(waf1/cip1) can determine if a cell undergoes apoptosis or cell cycle arrest following HDACi treatment. In the Eµ-myc transgenic mouse model of B-cell lymphoma, knockout of cdkn1a had no effect on disease latency, indicating that p21(waf1/cip1) did not function as a tumor suppressor in this system. Although HDACi robustly induced expression of p21(waf1/cip1) in wild-type Eµ-myc lymphomas, deletion of cdkn1a did not sensitize the lymphoma cells to HDACi-induced apoptosis and HDACi-induced cell cycle arrest still occurred. However, knockdown of cdkn1b in cdkn1a knockout lymphomas resulted in defective vorinostat-mediated arrest at G1/S indicating an essential role of p27(Kip1) in mediating this biological response to vorinostat. These data demonstrate that induction of cdkn1a does not regulate HDACi-mediated tumor cell apoptosis and refute the notion that p21(waf1/cip1) is an obligate mediator of HDACi-induced cell cycle arrest.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidores de Histona Desacetilases/farmacologia , Linfoma de Células B/genética , Linfoma de Células B/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Supressores de Tumor , Genes myc , Ácidos Hidroxâmicos/farmacologia , Linfoma de Células B/tratamento farmacológico , Masculino , Camundongos Knockout , Camundongos Transgênicos , VorinostatRESUMO
The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compounds that target the epigenome for the treatment of cancer. This notion is supported by biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through association with oncogenic fusion proteins such as PML-RARα and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biological and molecular responses of isogenic normal and transformed cells to the FDA-approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific molecules and pathways in the tumor-selective cytotoxic activity of these compounds.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular , Depsipeptídeos/toxicidade , Epigenômica , Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/toxicidade , Antígenos de Histocompatibilidade Menor , Neoplasias/metabolismo , Neoplasias/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , VorinostatAssuntos
Autofagia/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Animais , Fator Apoptótico 1 Ativador de Proteases/genética , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Proteína 5 Relacionada à Autofagia , Proteína 7 Relacionada à Autofagia , Linhagem Celular Tumoral , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Camundongos , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , VorinostatRESUMO
A novel series of potent blockers of the monocarboxylate transporter, MCT1, is disclosed. From very potent but lipophilic lead compounds, systematic changes to all parts of the molecule, targeting reduction in log D, afforded compounds with significantly improved overall properties. These compounds show potent immunomodulatory activity.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Herpesviridae/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Animais , Hidrocarboneto de Aril Hidroxilases/imunologia , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/imunologia , Doença Enxerto-Hospedeiro/imunologia , Herpesviridae/imunologia , Herpesviridae/metabolismo , Humanos , Fatores Imunológicos/química , Transportadores de Ácidos Monocarboxílicos/imunologia , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/imunologia , Simportadores/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
The cost-effectiveness of pharmacists and their effect on inpatient health care outcomes were evaluated. For one year, data were collected on all patients receiving care from general medicine and general surgery teams at Walter Reed Army Medical Center, Washington, D.C. Two of five medicine teams and one of three surgery teams included a pharmacist. Teams that included a pharmacist were compared with teams that did not, in terms of patients' length of stay (LOS), mortality, and drug cost per admission. Data were compared for 3081 patients and collected for another 557 who were not included in the comparative study design. Health care teams that included a pharmacist had a shorter log LOS and lower log drug cost per admission but no difference in mortality. The average cost savings for teams that included a pharmacist was $377 per inpatient admission, and the benefit-to-cost ratio was 6.03:1. The inclusion of pharmacists on health care teams was cost-effective and provided a favorable benefit-to-cost ratio.