Journal Article

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

Kimie Nakagawa, Yuko Sasaki, Shigeaki Kato, Noboru Kubodera and Toshio Okano

in Carcinogenesis

Volume 26, issue 6, pages 1044-1054
Published in print June 2005 | ISSN: 0143-3334
Published online February 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi049
22-Oxa-1α,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer

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1α,25-Dihydroxyvitamin D3 (1α,25-D3) 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-1α,25-dihydroxyvitamin D3 (22-oxa-1α,25-D3), 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 1α,25-D3, 22-oxa-1α,25-D3 or vehicle. The 1α,25-D3 treatment group had been hypercalcemic, but the 22-oxa-1α,25-D3 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 1α,25-D3 and 22-oxa-1α,25-D3-treated mice. In the in vitro experiment, 1α,25-D3 and 22-oxa-1α,25-D3 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 1α,25-D3 and 22-oxa-1α,25-D3-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-1α,25-D3 without other functions induced by 22-oxa-1α,25-D3 in the host. In the VDR−/− mice, 22-oxa-1α,25-D3 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-1α,25-D3 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-1α,25-D3. Our findings show that 22-oxa-1α,25-D3 is beneficial for the prevention of metastasis in lung carcinoma.

Keywords: 1α,25-D3, 1α,25-dihydroxyvitamin D3; GFP, green fluorescent protein; HHM, hormonal hypercalcemia of malignancy; LLC, Lewis lung carcinoma; MMP, matrix metalloproteinase; 22-oxa-1α,25-D3, 22-oxa-1α,25-dihydroxyvitamin D3; PKA, protein kinase A; PTHrP, parathyroid hormone-related peptide; VDR, vitamin D receptor; VEGF, vascular endothelial growth factor

Journal Article.  8750 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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