Sorafenib induces autophagy in human myeloid dendritic cells and prolongs survival of skin allografts.
BACKGROUND
Sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on the function of dendritic cells. This study was aimed to determine the effects of sorafenib on inducing autophagy and immunomodulatory activity and its implication on graft rejection.


METHODS
Cell viability and surface antigens were examined by 7-amino-actinomycin D and flow cytometric analysis. Autophagy was characterized using light microscopy and transmission electron microscopy for morphology, Western blotting for LC3B-I lipidation and mammalian target of rapamycin signaling molecules, and immunofluorescence staining for endogenous LC3B, GFP-LC3 transfection, and acidic component vacuoles. Skin allograft in mice was used as an experimental transplantation rejection model. Soluble factors contained in culture medium and serum were measured by enzyme-linked immunosorbent assay.


RESULTS
We found that sorafenib inhibited the viability of dendritic cells accompanied by morphologic changes characteristic of autophagy and immature differentiation. This autophagic effect induced by sorafenib was validated by LC3B-I lipidation and autophagosome accumulation. Sorafenib treatment was associated with the down-regulation of phosphorylated mammalian target of rapamycin and its downstream substrate p70S6K. We next performed skin graft model to testify the role of sorafenib-induced immature and autophagic dendritic cells. Intriguingly, sorafenib prolonged the survival of skin allograft without major toxicity. Blockade of autophagic flux by chloroquine partially diminished the protective effect of sorafenib, indicating an autophagy-related mechanism in vivo.


CONCLUSIONS
This study suggests that sorafenib, in addition to being an anticancer agent, may have potential to be developed as a new category of immunosuppressant drugs acting via autophagy induction of dendritic cells.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Jiunn-Chang
JC
Lin
Wei-Pang
WP
Huang
Chien-Liang
CL
Liu
Jie-Jen
JJ
Lee
Tsang-Pai
TP
Liu
Wen-Chin
WC
Ko
Yu-Chuen
YC
Huang
Ming-Ling
ML
Hsu
Chih-Hsiung
CH
Wu
Yu-Jen
YJ
Chen
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival; D003609:Dactinomycin / Q000031:analogs & derivatives / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D022423:Myeloid Cells / Q000187:drug effects*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016038:Skin Transplantation / Q000379:methods*; D000077157:Sorafenib; D014184:Transplantation, Homologous
D000941:Antigens; D007166:Immunosuppressive Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D003609:Dactinomycin; D009536:Niacinamide; C025942:7-aminoactinomycin D; D000077157:Sorafenib