RESUMO
To obtain further insights into the biological differences of anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK+ ALCL) and classical Hodgkin lymphoma (HL), we screened microbial culture filtrates to search for compounds that would exert a significantly greater effect on the viability of ALK+ ALCL cell lines compared to HL cell lines and identified Brefeldin A (BFA) as a suitable candidate. BFA inhibited phosphorylation of ALK and its downstream molecule, signal transducer and activator of transcription 3 (STAT3), one of the central pathways for the survival of ALK+ ALCL cells. In HL cell lines BFA did not affect CD30 expression or constitutive nuclear factor (NF)-κB activity, both of which are critical for HL cell survival. BFA induced disruption of the Golgi apparatus in ALK+ ALCL cell lines, which was accompanied by a decrease in active ADP-ribosylation factor 1 (ARF1), whereas BFA had no significant effect on these parameters in HL cell lines. These results add extra insights into the biological distinction between ALK+ ALCL and HL cells and highlight the Golgi apparatus as a target for the treatment of ALK+ ALCL.
Assuntos
Brefeldina A/farmacologia , Doença de Hodgkin/metabolismo , Linfoma Anaplásico de Células Grandes/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fator 1 de Ribosilação do ADP/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Expressão Gênica , Complexo de Golgi/efeitos dos fármacos , Doença de Hodgkin/genética , Humanos , Antígeno Ki-1/genética , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/genética , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/genética , Fator de Transcrição STAT3/antagonistas & inibidoresRESUMO
Quinofuracins A-E, novel anthraquinone derivatives containing ß-D-galactofuranose that were isolated from the fungus Staphylotrichum boninense PF1444, induced p53-dependent cell death in human tumor cells. The structures of quinofuracins A-E, including absolute configurations, were elucidated by extensive spectroscopic analysis and chemical transformation studies. Quinofuracins were classified into three groups according to the aglycone moieties. 5'-Oxoaverantin was present in quinofuracins A-C, whereas averantin and versicolorin B were identified in quinofuracins D and E, respectively. These quinofuracins induced p53-dependent growth suppression in human glioblastoma LNZTA3 cells.
Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Ascomicetos/química , Proteína Supressora de Tumor p53/metabolismo , Antraquinonas/química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/tratamento farmacológico , Humanos , Japão , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Proteína Supressora de Tumor p53/efeitos dos fármacosRESUMO
We have screened microbial culture filtrates for nitrogen monoxide (NO) production inhibitors using mouse macrophage cell line RAW264.7. As a result, paxilline, 21-isopentenylpaxilline and a novel analog of paxilline have been isolated from the culture filtrate of fungus Eupenicillium shearii. The novel analog possesses an additional dihydropyran ring, and was named as pyrapaxilline. This compound inhibited the NO production with lower toxicity than paxilline.
