Antiproliferative effects of 1alpha,25-dihydroxyvitamin D(3) and vitamin D analogs on tumor-derived endothelial cells.
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).
Bernardi
Ronald J
RJ
Department of Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania 15213, USA.
Johnson
Candace S
CS
Modzelewski
Ruth A
RA
Trump
Donald L
DL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002117:Calcitriol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005840:Gentian Violet; D007202:Indicators and Reagents; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D000804:Angiotensin II; D014807:Vitamin D; D003907:Dexamethasone; D002117:Calcitriol; D005840:Gentian Violet