RESUMO
Aberrant expression of the B lymphoid marker, CD19, in acute myeloid leukemia (AML) has frequently been associated with t(8;21)(q22;q22). However, AML cases lacking t(8;21) may occasionally express CD19. We asked whether CD19 expression is restricted to the karyotypically abnormal leukemic cells in primary leukemia samples. We compared, by fluorescence in situ hybridization, CD19-positive and CD19-negative cells from nine patients with acute leukemia: three non-t(8;21) AML, three t(8;21) AML and three cases of acute lymphoblastic leukemia. There were no significant differences in karyotypic pattern between the CD19-positive and CD19-negative leukemic cells, raising the concern that therapeutically targeting CD19 for acute leukemia may not eradicate all malignant clones.
Assuntos
Antígenos CD19/metabolismo , Aberrações Cromossômicas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Antígenos CD19/genética , Expressão Gênica , Humanos , Imunofenotipagem , Hibridização in Situ FluorescenteAssuntos
Doenças Autoimunes/prevenção & controle , Síndromes Mielodisplásicas/terapia , Linfócitos T Reguladores/patologia , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Doenças Autoimunes/complicações , Doenças Autoimunes/patologia , Azacitidina/uso terapêutico , Contagem de Células Sanguíneas , Regulação para Baixo , Humanos , Doença de Huntington/complicações , Doença de Huntington/diagnóstico , Doença de Huntington/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Linfócitos T Reguladores/imunologiaAssuntos
Cardiotoxinas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamente , Adulto , Benzamidas , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/secundário , Dasatinibe , Evolução Fatal , Feminino , Humanos , Mesilato de Imatinib , Cromossomo Filadélfia , Piperazinas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirimidinas/efeitos adversos , Tiazóis/efeitos adversosRESUMO
Aminoflavone (5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methylchromen-4-one; AF; NSC 686288), a novel anticancer candidate agent, is undergoing clinical evaluation. AF induces DNA-protein cross-links (DPCs), Gamma-H2AX phosphorylation, aryl hydrocarbon receptor (AhR) signaling, apoptosis and its own metabolism via cytochrome P4501A1 and 1A2 (CYP1A1/1A2) activation in sensitive estrogen receptor positive (ER+) MCF7 breast cancer cells. Estrogen receptor negative (ER-) breast cancer is typically more aggressive with a poorer prognosis. In this investigation, we evaluated the ability of AF to induce reactive oxygen species (ROS) formation, oxidative DNA damage and apoptosis in ER- MDA-MB-468 breast cancer cells. The antioxidant, N-acetyl-L-cysteine (NAC), attenuated the cytotoxic effects of AF in MDA-MB-468 cells; an effect is also observed in ER+ T47D breast cancer cells. Nonmalignant MCF10A breast epithelial cells were resistant to the cytotoxic effects of AF. AF increased intracellular ROS, an effect blocked by NAC and the CYP1A1/1A2 inhibitor, alpha-Naphthoflavone (alpha-NF). AF induced oxidative DNA damage as evidenced by increased 8-oxo-7,8-dihydroguanine (8-oxodG) levels and DPC formation in these cells. AF caused S-phase arrest corresponding to an increase in p21((waf1/cip1)) protein expression. AF induced caspase 3, 8 and 9 activation, caspase-dependent apoptotic body formation and poly [ADP-ribose] polymerase (PARP) cleavage. Pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp(OMe)-fluoromethylketone inhibited apoptosis and partially inhibited ROS formation and oxidative DNA damage. Pretreatment with NAC attenuated AF-induced apoptotic body formation and caspase 3 activation. These studies suggest AF inhibits the growth of breast cancer cells in part, by inducing ROS production, oxidative DNA damage and apoptosis and has the potential to treat hormone-independent breast cancer.