ビタミンDおよびビタミンKを分子基盤とするがんおよび骨粗鬆症治療薬の開発研究

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1α,25-Dihydroxyvitamin D_3[1α,25(OH)_2D_3], the major regulator of calcium homeostasis, has potent antiproliferative and anti-invasive properties in vitro in cancer cells. Little information is available concerning structural motifs of the 1α,25(OH)_2D_3 molecule responsible for modulation of differentiation and apoptosis. We synthesized all possible A-ring diastereomers of the singly dehydroxylated 19-nor-1α,25(OH)_2D_3, 2-methyl-1α,25(OH)_2D_3 and its 20-epimer and evaluated their biological activities in human promyelocytic leukemia (HL-60) cells. We have clearly identified for the first time the structural motifs on the basis of the stereochemistry of both hydroxyl groups at positions 1 and 3 of the A-ring of the 1α,25(OH)_2D_3 molecule responsible for the inductions of differentiation and apoptosis of HL-60 cells. In vivo studies demonstrated that 1α,25(OH)_2D_3 slowed the progression of breast, prostate, and other carcinomas. A key question was whether 1α,25(OH)_2D_3 exerts its anticarcinogenic effects in vivo by a mechanism that is dependent on its capacity to limit the proliferation and invasiveness of cancer cells in vitro. We used metastatic Lewis lung carcinoma cells expressing green fluorescent protein (LLC-GFP cells) and examined the metastatic activity in vitamin D receptor (VDR) null mutant (VDR-/-) mice and their wild-type counterparts (VDR+/+mice). VDR-/- mice exhibited hypocalcemia and extremely high serum levels of 1α,25(OH)_2D_3. The metastatic growth of LLC-GFP cells was remarkably reduced in response to the serum levels of 1α,25(OH)_2D_3 but not to the serum levels of calcium. We showed that 1α,25(OH)_2D_3 inhibited the metastatic growth of lung cancer cells in a defined animal model. There are two forms of naturally occurring vitamin K, phylloquinone and menaquinones. Phylloquinone (vitamin K_1) is the major type (>90%) of dietary vitamin K, but its concentrations in animal tissues are remarkably low compared with those of menaquinones, especially menaquinone-4 (vitamin K_2), the major form (>90%) of vitamin K in tissues. Despite this great difference, the origin of tissue menaquinone-4 has yet to be exclusively defined. It is postulated that phylloquinone is converted into menaquinone-4 and accumulates in extrahepatic tissues. To clarify this, phylloquinone with a deuterium-labeled 2-methyl-1,4-naphthoquinone ring was given orally to mice and cerebra were collected for D NMR and LC-MS/MS analyses. We identified the labeled menaquinone-4 that was converted from the given phylloquinone. Our results may aid in the clarification of the physiological role of MK-4 in the brain and the development of new drugs for the treatment of neuronal diseases.
2011-01-25

ビタミンDおよびビタミンKを分子基盤とするがんおよび骨粗鬆症治療薬の開発研究

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