Sorafenib induces autophagy in human myeloid dendritic cells and prolongs survival of skin allografts
作者： Jiunn-Chang Lin , Wei-Pang Huang , Chien-Liang Liu , Jie-Jen Lee , Tsang-Pai Liu
DOI: 10.1097/TP.0B013E31827FAC48
关键词:
摘要: BACKGROUND Sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on function dendritic cells. This study was aimed to determine effects sorafenib inducing autophagy immunomodulatory activity its implication graft rejection. METHODS Cell viability surface antigens were examined by 7-amino-actinomycin D flow cytometric analysis. Autophagy characterized using light microscopy transmission electron morphology, Western blotting LC3B-I lipidation mammalian target rapamycin signaling molecules, immunofluorescence staining endogenous LC3B, GFP-LC3 transfection, acidic component vacuoles. Skin allograft in mice used as an experimental transplantation rejection model. Soluble factors contained culture medium serum measured enzyme-linked immunosorbent assay. RESULTS We found that inhibited cells accompanied morphologic changes characteristic immature differentiation. autophagic effect induced validated autophagosome accumulation. Sorafenib associated with down-regulation phosphorylated downstream substrate p70S6K. next performed skin model testify role sorafenib-induced Intriguingly, prolonged survival without major toxicity. Blockade flux chloroquine partially diminished protective sorafenib, indicating autophagy-related mechanism vivo. CONCLUSION suggests addition being anticancer agent, may have potential be developed new category immunosuppressant drugs acting via induction
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