Elucidation of the mechanism of cancer cell metastasis and permeation using active vitamin D as a molecular base and development of therapeutic agents

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In the present study, we demonstrated from the in vitro and in vivo studies that 1α,25-dihydroxyvitamin D_3 (1α,25-D_3) and its derivatives are effective for the prevention and treatment of cancer. The results were follows. (1) It was found that 22-oxa-calcitriol, a low calcemic vitamin D analogue used clinically for the treatment of psoriasis and secondary hyperparathyroidism, is inactivated via through the pathway of either side-chain dehydration or isomerization of a hydroxy group at C-3 of the A-ring. In addition, it was found that the putative enzymes involved in the above pathways regulate the metabolism of la,25-D_3 cooperatively. (2) We confirmed that due to the lack of appropriate explanation for species difference (from animals to humans) of our results, employments of known-vitamin D metabolic enzymes expression systems were useful for the screening of the biological activity of vitamin D compounds. (3) We clarified that la,25-D_3 inhibits the growth of LLC-GFP cells by thro … More ugh the induction of G1 arrest, and inhibits the metastasis of cancer cells via the inhibition of MMP-2 and -9 expression, and suppress the angiogenesis of cancer cells via the inhibition of the expression of angiogenesis-inducing factors. (4) We clarified that using VDR gene targeting mice as a an animal model for the evaluation of cancer cell growth, l a,25-D_3 suppressed the tumor growth of LLC-GFP cells, which are VDR-positive, and the anti-tumorigenesis of l a,25-D_3 did not require the involvement of its calcemic action, and at both supraphysiological and normal serum concentrations, 1α,25-D_3 effectively suppressed the tumor growth. (5) I was found that 22-oxa-calcitriol suppressed the LLC-GFP cell growth without inducing any calcemic symptoms in animals. By the present study, we established the distinguished experimental model system for the screening of the anti-cancer activity of active vitamin D at gene, cellular and animal levels. Using these methods, it can be expected that the inter-cooperation between biology group and chemistry group will creates novel vitamin D analogues, especially having superior anti-cancer activity.In the present study, we demonstrated from the in vitro and in vivo studies that 1α,25-dihydroxyvitamin D_3 (1α,25-D_3) and its derivatives are effective for the prevention and treatment of cancer. The results were follows. (1)It was found that 22-oxa-calcitriol, a low calcemic vitamin D analogue used clinically for the treatment of psoriasis and secondary hyperparathyroidism, is inactivated via through the pathway of either side-chain dehydration or isomerization of a hydroxy group at C-3 of the A-ring. In addition, it was found that the putative enzymes involved in the above pathways regulate the metabolism of 1α,25-D_3 cooperatively. (2)We confirmed that due to the lack of appropriate explanation for species difference (from animals to humans) of our results, employments of known-vitamin D metabolic enzymes expression systems were useful for the screening of the biological activity of vitamin D compounds. (3)We clarified that 1α,25-D_3 inhibits the growth of LLC-GFP cells by through the induction of G1 arrest, and inhibits the metastasis of cancer cells via the inhibition of MMP-2 and -9 expression, and suppress the angiogenesis of cancer cells via the inhibition of the expression of angiogenesis-inducing factors. (4)We clarified that using VDR gene targeting mice as a an animal model for the evaluation of cancer cell growth, 1α,25-D_3 suppressed the tumor growth of LLC-GFP cells, which are VDR-positive, and the anti-tumorigenesis of 1α,25-D_3 did not require the involvement of its calcemic action, and at both supraphysiological and normal serum concentrations, 1α,25-D_3 effectively suppressed the tumor growth. (5)I was found that 22-oxa-calcitriol suppressed the LLC-GFP cell growth without inducing any calcemic symptoms in animals. By the present study, we established the distinguished experimental model system for the screening of the anti-cancer activity of active vitamin D at gene, cellular and animal levels. Using these methods, it can be expected that the inter-cooperation between biology group and chemistry group will creates novel vitamin D analogues, especially having superior anti-cancer activity. Less