Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate.
Thalidomide, which is clinically recognized as an efficient therapeutic agent for multiple myeloma, has been thought to exert antiangiogenic action through an unknown mechanism. We here show a novel mechanism of thalidomide-induced antiangiogenesis in zebrafish embryos. Thalidomide induces the defect of major blood vessels, which is demonstrated by their morphologic loss and confirmed by the depletion of vascular endothelial growth factor (VEGF) receptors such as neuropilin-1 and Flk-1. Transient increase of ceramide content through activation of neutral sphingomyelinase (nSMase) precedes thalidomide-induced vascular defect in the embryos. Synthetic cell permeable ceramide, N-acetylsphingosine (C2-ceramide) inhibits embryonic angiogenesis as well as thalidomide. The blockade of ceramide generation by antisense morpholino oligonucleotides for nSMase prevents thalidomide-induced ceramide generation and vascular defect. In contrast to ceramide, sphingosine-1-phosphate (S1P) inhibits nSMase-dependent ceramide generation and restores thalidomide-induced embryonic vascular defect with an increase of expression of VEGF receptors. In human umbilical vein endothelial cells (HUVECs), thalidomide-induced inhibition of cell growth, generation of ceramide through nSMase, and depletion of VEGF receptors are restored to the control levels by pretreatment with S1P. These results suggest that thalidomide-induced antiangiogenic action is regulated by the balance between ceramide and S1P signal.
Yabu
Takeshi
T
Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Japan.
Tomimoto
Hidekazu
H
Taguchi
Yoshimitsu
Y
Yamaoka
Shohei
S
Igarashi
Yasuyuki
Y
Okazaki
Toshiro
T
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018076:DNA, Complementary; D004625:Embryo, Nonmammalian / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005124:Eye Abnormalities / Q000139:chemically induced; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism; D016376:Oligonucleotides, Antisense; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D013792:Thalidomide / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D015027:Zebrafish
D020533:Angiogenesis Inhibitors; D018076:DNA, Complementary; D008246:Lysophospholipids; C064769:N-acetylsphingosine; D016376:Oligonucleotides, Antisense; D039942:Neuropilin-1; C060506:sphingosine 1-phosphate; D013792:Thalidomide; D040301:Vascular Endothelial Growth Factor Receptor-2; D013108:Sphingomyelin Phosphodiesterase; D008274:Magnesium; D013110:Sphingosine