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Antiproliferative
effects of 1alpha,25-dihydroxyvitamin D(3) and vitamin D analogs on
tumor-derived endothelial cells
Bernardi RJ, Johnson CS, Modzelewski RA, Trump DL
Department of Pharmacology, University of Pittsburgh Cancer
Institute, University of Pittsburgh, Pennsylvania 15213, USA
Although there is abundant evidence that 1alpha,25-dihydroxyvitamin D(3)
[1,25-(OH)(2)D(3)] inhibits the growth of several cancer cell types, inhibition
of angiogenesis may also play a role in mediating the antitumor effects of
1,25-(OH)(2)D(3).
We examined the ability of 1,25-(OH)(2)D(3) to inhibit the growth of
tumor-derived endothelial cells (TDECs) and normal endothelial cells and to
modulate angiogenic signaling.
1,25-(OH)(2)D(3) inhibited the growth of TDECs from two tumor models at
nanomolar concentrations, but was less potent against normal aortic or yolk sac
endothelial cells.
The vitamin D analogs Ro-25-6760, EB1089, and ILX23-7553 were also potent
inhibitors of TDEC proliferation.
Furthermore, the combination of 1,25-(OH)(2)D(3) and dexamethasone had greater
activity than either agent alone.
1,25-(OH)(2)D(3) increased vitamin D receptor and p27(Kip1) protein levels in
TDECs, whereas phospho-ERK1/2 and phospho-Akt levels were reduced.
These changes were not observed in normal aortic endothelial cells.
In squamous cell carcinoma and radiation-induced fibrosarcoma-1 cells,
1,25-(OH)(2)D(3) treatment caused a reduction in the angiogenic signaling
molecule, angiopoietin-2.
In conclusion, 1,25-(OH)(2)D(3) and its analogs directly inhibit TDEC
proliferation at concentrations comparable to those required to inhibit tumor
cells.
Further, 1,25-(OH)(2)D(3) modulates cell cycle and survival signaling in TDECs
and affects angiogenic signaling in cancer cells.
Thus, our work supports the hypothesis that angiogenesis inhibition plays a role
in the antitumor effects of 1,25-(OH)(2)D(3).
PMID: 12072382 [PubMed - indexed for MEDLINE]
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