Page 116 - Vitamin D and Cancer

5 Vitamin D and Angiogenesis 103

a synthetic glutamic acid derivative that inhibits the expression of VEGF and beta
fibroblast growth factor and thus suppressing angiogenesis [63].
The standard maximum tolerated dose (MTD) chemotherapy requires long
drug-free intervals for bone marrow recovery. In contrast, angiogenesis inhibitors
are administered with a low-dose metronomic regimen without breaks [1].
Chemotherapy usually targets dividing cells and does not differentiate tumor cells
and normal cells, thereby causing more severe side effects such as bone marrow
suppression, severe vomiting, and diarrhea. Compared with classic chemotherapeu-
tic drugs, angiogenesis inhibitors have several advantages. They target high levels
of angiogenesis as found in tumors, and the stable vasculature of the host is spared.
Therefore, their side effects are usually mild and include thrombotic complications,
intratumoral bleeding, hypertension, and peripheral neuropathy [1]. They do inter-
fere with fetal development and wound healing since these processes also depend
on angiogenesis. Tumor resistance to angiogenesis inhibitors is not as common as
with chemotherapy. Angiogenesis inhibitors have been reported to enhance the
antitumor activity of some standard chemotherapy agents [56, 64, 65]. Notably,
every class of chemotherapeutic drugs has been shown to have anti-angiogenic
effects in either in vitro or in vivo angiogenesis assays [66].

5.2 Vitamin D Effects on Angiogenesis

5.2.1 VDR Expression in Cells of Vasculature

Both endothelial cells [67–69] and vascular smooth muscle cells (VSMCs) [70–74]
have been demonstrated to express functional vitamin D receptor (VDR). High-
affinity VDR is detected in cultured bovine aortic endothelial cells using
receptor-binding assays [67]. Immunoblot analysis shows that VDR protein is
expressed endogenously and readily induced by 1,25D , the active metabolite of
3
vitamin D, in endothelial cells isolated from Matrigel plugs or murine squamous
cell carcinoma (SCC) [69]. Receptor-binding assay and immunoblot analysis reveal
the expression of VDR in VSMCs [70, 73]. 1a-Hydroxylase (1a-OHase), the enzyme
that leads to local production of 1,25D from its precursor 25(OH)D , is expressed
3 3
in endothelial cells isolated from human renal arteries, postcapillary venules from
lymphoid tissue, and human umbilical vein endothelial cells (HUVEC) [75]. The
1a-OHase expressed in endothelial cells is enzymatically active since treatment
with 1,25D or 25(OH)D suppresses HUVEC proliferation [75].
3 3

5.2.2 Effect on Endothelial Cells

1,25D suppresses VEGF-induced proliferation of bovine aortic endothelial cells.
3
It also reduces VEGF-induced endothelial cell sprouting and elongation in vitro