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Antiproliferative Effects of 1,25-Dihydroxyvitamin D₃ and Vitamin D Analogs on Tumor-Derived Endothelial Cells

Departments of Pharmacology (R.J.B., C.S.J., R.A.M.), Medicine (C.S.J., D.L.T.), and Urology (D.L.T.), University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Dr. Donald L. Trump, Department of Medicine, University of Pittsburgh, UPMC Montefiore, N723, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213. E-mail: . trumpdl{at}msx.upmc.edu

Although there is abundant evidence that 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] 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)₂D_3. We examined the ability of 1,25-(OH)₂D₃ to inhibit the growth of tumor-derived endothelial cells (TDECs) and normal endothelial cells and to modulate angiogenic signaling. 1,25-(OH)₂D₃ 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)₂D₃ and dexamethasone had greater activity than either agent alone. 1,25-(OH)₂D₃ 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)₂D₃ treatment caused a reduction in the angiogenic signaling molecule, angiopoietin-2. In conclusion, 1,25-(OH)₂D₃ and its analogs directly inhibit TDEC proliferation at concentrations comparable to those required to inhibit tumor cells. Further, 1,25-(OH)₂D₃ 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)₂D₃.

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