Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis.
In multiple myeloma (MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM. We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells (HUVECs). Five myeloma cell lines produced varying amounts of VEGF, and migration of HUVECs was induced by coculture with myeloma cells. We next examined the inhibitory effect of a novel synthetic retinoid Am80 (Tamibarotene) on both myeloma cells and HUVECs. Am80 is specific for the retinoic-acid receptor-alpha/beta, and has therapeutic effects in all-trans retinoic acid resistant acute promyelocytic leukemia. Am80 slightly inhibited the growth of both myeloma cells and HUVECs, and remarkably inhibited the growth of HUVECs stimulated by VEGF. Am80 showed little growth inhibition of bone marrow stromal cells (BMSCs), but it markedly inhibited migration of HUVECs by cocultured myeloma cells. Am80 inhibited VEGF-induced phosphorylation of VEGF receptor. In addition, VEGF-induced formation of tube-like structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80. These findings clearly demonstrate that Am80 is a potential inhibitor of angiogenesis caused by the interaction between vascular endothelial cells and myeloma cells, and might be a useful therapeutic agent against MM.
Sanda
T
T
Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Kuwano
T
T
Nakao
S
S
Iida
S
S
Ishida
T
T
Komatsu
H
H
Shudo
K
K
Kuwano
M
M
Ono
M
M
Ueda
R
R
D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D003315:Cornea / Q000098:blood supply* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D001565:Benzoates; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D042461:Vascular Endothelial Growth Factor A; C061133:tamibarotene; D040262:Receptors, Vascular Endothelial Growth Factor