1 Alpha,25-dihydroxyvitamin D3 and its TX527 analog inhibit the growth of endothelial cells transformed by Kaposi sarcoma-associated herpes virus G protein-coupled receptor in vitro and in vivo.
The Kaposi sarcoma-associated herpes virus-G protein-coupled receptor is a key molecule in the pathogenesis of Kaposi sarcoma, playing a central role in promoting vascular endothelial growth factor-driven angiogenesis and spindle cell proliferation. We studied the effects of 1 alpha,25-dihydroxyvitamin D(3) [1 alpha,25(OH)(2)D(3)] and the analog TX527 on the proliferation of endothelial cells (SVECs) and SVECs transformed by the viral G protein-coupled receptor (SVEC-vGPCR). 1 alpha,25(OH)(2)D(3) and TX527 decreased SVEC-vGPCR and SVEC numbers, the response being time dependent and similar in both cell lines. Vitamin D receptor (VDR) levels increased on treatment with 10 nm 1 alpha,25(OH)(2)D(3) or 1 nm TX527 in a time-dependent manner (1.5-24 h) in SVECs and SVEC-vGPCR. Basal VDR levels were increased in SVEC-vGPCR. The antiproliferative effects were accompanied by reduction in cyclin D1 and accumulation of p27 in SVECs but not SVEC-vGPCR. Induction of VDR was blocked by transfection of short hairpin RNA against VDR in SVEC-vGPCR and the antiproliferative effects of 1 alpha,25(OH)(2)D(3) and TX527 were decreased, involving the VDR genomic pathway in the hormone and analog mechanism of action. In vivo experiments showed that 1 alpha,25(OH)(2)D(3) and TX527 decreased SVEC-vGPCR tumor progression when the tumor cells were implanted in nude mice. In conclusion, we have demonstrated that 1 alpha,25(OH)(2)D(3) and its TX527 analog have antiproliferative effects on the growth of endothelial cells transformed by the vGPCR in vitro and in vivo, the vitamin D receptor being part of the inhibitory mechanism of action.
Gonzalez-Pardo
Verónica
V
Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, 8000 Bahía Blanca, Argentina.
Martin
Daniel
D
Gutkind
J Silvio
JS
Verstuyf
Annemieke
A
Bouillon
Roger
R
de Boland
Ana Russo
AR
Boland
Ricardo L
RL
D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects*; D002472:Cell Transformation, Viral / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
D000480:Alkynes; C115448:G protein-coupled receptor, Human herpesvirus 8; D018167:Receptors, Calcitriol; D019707:Receptors, Chemokine; C118756:dihydroxy-vitamin D3; C409043:inecalcitol; D014807:Vitamin D; D002762:Cholecalciferol