RESUMO
BACKGROUND: Sorafenib, a multi-kinase inhibitor approved for treatment of advanced renal cell carcinoma and other malignancies, has been shown as a modulator for dendritic cells. This study was designed to examine the effects of sorafenib on macrophages, the major ontogeny of innate immunity. MATERIALS AND METHODS: Macrophages were derived from sorted CD14(+) monocytes of human peripheral blood mononuclear cells. Cell viability and surface antigens were examined by trypan blue analysis. Autophagy was characterized by light microscopy and transmission electron microscopy for morphology, Western blotting for microtubule associated light chain protein 3B (LC-3B) I lipidation, and acridine orange staining for acidic component vacuoles. Soluble factors contained in culture medium and serum were measured by ELISA. RESULTS: We found that sorafenib inhibited the viability of macrophages accompanied by morphological changes characteristic of autophagy. This autophagy-inducing effect was validated by LC3B-I lipidation and autophagosome accumulation. The surface antigen expression and the function of activated macrophages were inhibited by sorafenib, including the expression of co-stimulatory molecule CD80, phagocytosis, and the production of reactive oxygen species. The secretion of IL-10, but not IL-6, TNF-α nor TGF-ß, was reduced by sorafenib. CONCLUSION: Sorafenib, in addition to being a cancer targeted therapeutic agent, can induce autophagy and modulate the function of human macrophages.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/imunologia , Regulação para Baixo , Humanos , Imunidade Inata/efeitos dos fármacos , Terapia de Imunossupressão , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/imunologia , Terapia de Alvo Molecular , Niacinamida/farmacologia , Espécies Reativas de Oxigênio/metabolismo , SorafenibeRESUMO
To compare immunologic phenotypes between (1) hepatocellular carcinoma (HCC) patients and a healthy population and (2) more advanced and early stage HCC patients, we studied 45 HCC patients and 46 healthy controls from January 2006 to January 2008. Using fluorescent activated cell sorter (FACS) analysis, HCC patients were demonstrated to exhibit stronger phagocytosis of granulocytes and monocytes and more peripheral blood mononuclear cells (PBMCs) in the G2/M phase compared with healthy volunteers. By contrast, lower percentages of B and T(h) lymphocytes were also found in the peripheral blood of HCC patients than in the healthy population. Most importantly, a higher percentage of B cells was found in patients with advanced HCC than in those with early HCC in terms of TNM stage (II and III vs I, p = 0.004), the Japanese Integrated Scoring system (2-3 vs 0-1, p = 0.0235), and tumor numbers (> or =2 vs 1, p = 0.005). In conclusion, our findings suggested that HCC patients might exhibit enhanced innate immunity and reduced adaptive immunity compared with healthy volunteers. A higher percentage of B cells was found in patients with more advanced HCC compared with patients with early stage HCC, which might serve as an indicator of the severity of HCC.
