Inhibition of angiogenesis as a mechanism for inhibition by Lα‐hydroxyvitamin D3 and 1,25‐dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats

Abstract

The effects of 1α‐hydroxyvitamin D3[1α(OH)D3] and 1,25‐dihydroxyvitamin D3[1,25(OH)2D3] on the incidence of colon tumors induced by azoxymethane and on the labeling index and angiogenesis of colon tumors were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of azoxymethane and i.p. injections of 1α(OH)D3 and 1,25(OH)2D3 at lower and higher doses every other day for 45 weeks. Prolonged administration of both 1α(OH)D3 and 1,25(OH)2D3 at a higher dose significantly reduced the incidence of colon tumors in week 45. However, administration of 1α(OH)D3 or 1,25(OH)2D3 had little or no effect on the histologic type of colon tumors and cancers. Administration of 1α(OH)D3 and 1,25(OH)2D3 at higher doses significantly decreased the labeling index, the immuno‐histochemical staining for vascular endothelial growth factor and microvessel counts in colon tumors. Our findings suggest that both 1α(OH)D3 and 1,25(OH)2D3 inhibit development of colon tumors. A possible mechanism of inhibition of colon carcinogenesis by 1α(OH)D3 and 1,25(OH)2D3 is the inhibition of angiogenesis as well as an anti‐proliferative effect. Int. J. Cancer 81:730–733, 1999. © 1999 Wiley‐Liss, Inc.

Vitamin D inhibits growth of human airway smooth muscle cells through growth factor‐induced phosphorylation of retinoblastoma protein and checkpoint kinase 1

“…Because the anti-proliferative effects of calcitriol in ASM could be mediated by preventing phosphorylation of Rb, we next examined known modulators of Rb phosphorylation such as cyclin D. Surprisingly, calcitriol had no effect on PDGF-induced cyclin D expression. In other cell types, growth factor-induced cyclin D expression was markedly inhibited by calcitriol (Iseki et al, 1999). As calcitriol inhibited ASM cell proliferation and cell cycle progression that appeared to occur prior to the S phase, we determined whether specific cell cycle inhibitors were affected by calcitriol.…”

“…In a variety of cell types, vitamin D manifests antiproliferative and/or pro-apoptotic actions. In some, but not all, cancer cell lines, vitamin D inhibits cell proliferation (Merke et al, 1989;Iseki et al, 1999;Mantell et al, 2000;Bernardi et al, 2002;Furigay and Swamy, 2004). In normal keratinocytes, however, calcitriol has little effect on cell growth while inhibiting keratinocytes derived from subjects who have psoriasis (Kragballe and Wildfang, 1990).…”

“…In normal keratinocytes, however, calcitriol has little effect on cell growth while inhibiting keratinocytes derived from subjects who have psoriasis (Kragballe and Wildfang, 1990). In endothelial cells, calcitriol inhibits cell growth and is antiangiogenic in vitro and in vivo in a number of tumour model systems (Merke et al, 1989;Iseki et al, 1999;Mantell et al, 2000;Bernardi et al, 2002;Furigay and Swamy, 2004). In a prostate cancer model, calcitriol also has anti-tumour activity in vivo; however, PC3 cells are relatively insensitive to the inhibitory effects of calcitriol .…”

Epidemiological Evidence for Vitamin D and Colorectal Cancer

“…Subsequently, a large number of studies have found that many cell types contain vitamin D receptors; furthermore, when these receptors are activated by 1,25(OH) 2 D, the most active metabolite of vitamin D, they induce potential cancer protective properties such as increasing differentiation and inhibiting prolif-eration, invasiveness, angiogenesis, and metastatic potential. (6)(7)(8)(9) Circulating 25(OH)D was shown to be potentially beneficial, because many cell types including cancer cells express 1-␣-hydroxylase, which is required to convert 25(OH)D into 1,25(OH) 2 D. This brief review considers the current epidemiological evidence of the role of vitamin D for the potential prevention of colorectal cancer.…”

Vitamin D: The Immunologic Role and its Effect on Human Pathophysiology

“…Vitamin D and its metabolites reduce the incidence of many types of cancer by inhibiting tumor angiogenesis, (Iseki et al, 1999;Majewski et al, 1996;Shokravi et al, 1995;Mantell et al, 2000) stimulating mutual adherence of cells, (Palmer et al, 2001) and enhancing intercellular communication through gap junctions, (Fujioka et al, 2000) thereby strengthening the inhibition of proliferation that results from tight physical contact with adjacent cells within a tissue (contact inhibition). Vitamin D metabolites help maintain a normal calcium gradient in the colon epithelial crypts, (Palmer et al, 2001) and high serum levels of 25(OH)D are associated with markedly decreased proliferation of noncancerous but high-risk epithelial cells in the colon (Lipkin and Newmark, 1985;Holt et al, 2002).…”