22-Oxa-1α,25-dihydroxyvitamin D 3 inhibits metastasis and angiogenesis in lung cancer

Abstract

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25-D(3)) has potent antiproliferative and anti-invasive properties in vitro in cancer cells. However, its calcemic effect in vivo limits its therapeutic applications. Here, we report the efficacy of 22-oxa-1alpha,25-dihydroxyvitamin D(3) (22-oxa-1alpha,25-D(3)), a low calcemic analog of vitamin D, against the development of metastatic lung carcinoma after an intravenous injection of green fluorescent protein-transfected Lewis lung carcinoma (LLC-GFP) cells in C57BL/6 mice. The mice injected with tumor cells were implanted simultaneously with osmotic minipumps containing either 1alpha,25-D(3), 22-oxa-1alpha,25-D(3) or vehicle. The 1alpha,25-D(3) treatment group had been hypercalcemic, but the 22-oxa-1alpha,25-D(3) and vehicle treatment groups remained normocalcemic for the duration of the experiment. The total number of lung metastases, lung weight and the expression of GFP mRNA in the lung were markedly decreased in 1alpha,25-D(3) and 22-oxa-1alpha,25-D(3)-treated mice. In the in vitro experiment, 1alpha,25-D(3) and 22-oxa-1alpha,25-D(3) reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial growth factor and parathyroid hormone-related protein in LLC-GFP cells. Furthermore, in the angiogenesis assay, the number of tumor cells or basic fibroblast growth factor-induced angiogenesis was reduced in 1alpha,25-D(3) and 22-oxa-1alpha,25-D(3)-treated mice. Moreover, using a new experimental model of vitamin D receptor (VDR) null mutant (VDR(-/-)) mice with corrected hypocalcemia and hypervitaminosis D, we examine the anti-cancer effect of 22-oxa-1alpha,25-D(3) without other functions induced by 22-oxa-1alpha,25-D(3) in the host. In the VDR(-/-) mice, 22-oxa-1alpha,25-D(3) directly inhibited the metastatic activity of LLC-GFP cells in a dose-dependent manner without exerting a direct influence on the calcemic activity or other actions regulated by 22-oxa-1alpha,25-D(3) in the host. These results indicate that the inhibition of metastasis and angiogenesis-inducing activity in cancer cells seemed to be a major mechanism responsible for the anti-cancer effects of 22-oxa-1alpha,25-D(3). Our findings show that 22-oxa-1alpha,25-D(3) is beneficial for the prevention of metastasis in lung carcinoma.

22‐Oxa‐1,25‐dihydroxyvitamin D3 efficiently inhibits tumor growth in inoculated mice and primary histoculutre of cholangiocarcinoma

“…The antitumor activity of 22-oxa-D 3 was more obvious in our mouse model than in cell cultures. The enhancement of 22-oxa-D 3 activity and its role in suppressing tumor growth in vivo can be explained by the finding that, apart from inducing cell cycle arrest as a result of enhanced expression of the cyclin-dependent kinase inhibitors p21 WAF1 and p27 Kip1 , 23,24 , a variety of mechanisms, including the regulation of angiogenesis, 25 increased apoptosis, 26 and reduced tumor invasiveness, 25,27 reportedly responsible for the actions of 1,25(OH) 2 D 3 . These latter 3 mechanisms could not be demonstrated in our CCA cell culture studies.…”

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact

“…In vitro, vitamin D down-regulates the activity of NF-KBETA activity [242] and stimulates anti-inflammatory cytokines [239,243]. Additionally, vitamin D-binding proteins are more evident in proximity to endothelium injury [244], inhibiting the expression of MMP-2, MMP-9 and of the endothelium growth factor [245]; they probably diminish the activity of platelet derived growth factor, conversely up-regulating thrombomodulin [246][247]. The second study, entirely dedicated to small vessel disease and vitamin D [224] lights some shadows in a fascinating problem: it presents a well-known association between bone small vessel disease and osteoporosis.…”

Vitamin D Status and the Risk of Lung Cancer: A Cohort Study in Finland

“…Animal and in vitro studies have shown that vitamin D can suppress tumor progression by reducing cell proliferation, invasiveness, and angiogenesis and stimulating apoptosis and cell differentiation (3)(4)(5). It has also reported to protect against metastasis in various tumor models, including cancer of the lung (3,5).…”