Enhancement of antiproliferative activity of 1 alpha,25-dihydroxyvitamin D-3 (analogs) by cytochrome P450 enzyme inhibitors is compound- and cell-type specific

被引:34
作者
Zhao, J [1 ]
Tan, BK [1 ]
Marcelis, S [1 ]
Verstuyf, A [1 ]
Bouillon, R [1 ]
机构
[1] CATHOLIC UNIV LEUVEN,EXPTL MED & ENDOCRINOL LAB,B-3000 LOUVAIN,BELGIUM
关键词
D O I
10.1016/0960-0760(95)00256-1
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ketoconazole (keto) or liarozole (liaro), inhibitors of the cytochrome P450 enzymes that mediate vitamin D and A hydroxylations, could potentiate the antiproliferative effects of 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3] and its analogs. Proliferation of MCF-7 and T47-D human breast cancer cells, MG-63 human osteosarcoma. cells and HL-60 human promyeloid leukemia cells was concentration dependently inhibited by 1 alpha,25(OH)(2)D-3. The vitamin D analogs KH 1060 [20-epi-22-oxa-24,26,27-trihomo-1 alpha,25(OH)(2)D-3], RO 23-6010 [16-ene-23-yne-26-trifluoro-1,25(OH)(2)D-3], ZXY 835 [20-epi-23-yne-25,26-epoxy-1 alpha(OH)D-3], and CD 99 [11 alpha-methyl-1 alpha,25(OH)(2)D-3] were 150-, 58-, 16- and 7-fold more potent than 1 alpha,25(OH)(2)D-3 in inhibiting the proliferation of MCF-7 cells, respectively. A similar rank order of potency was observed in other cell lines. The antiproliferative effects of the vitamin D hormone and analogs was enhanced in MCF-7 cells when coincubated with 1 mu M keto (7-, 10-, 5-, 25- and 1.3-fold more potent than in the absence of keto), respectively. The antiproliferative effect was less enhanced when 1 alpha,25(OH)(2)D-3 or its analogs KH 1060, ZXY 835 and RO 23-6010 were combined with liaro (3-, 7-, 2- and 3-fold, respectively). Keto and liaro did not markedly potentiate the activity of 1 alpha,25(OH)(2)D-3 or its analogs in MG-63 or HL-60 cells. These results suggest that differences in cellular metabolism can at least partially explain the different potency of vitamin D analogs. Moreover, the metabolism of vitamin D analogs is cell-type specific. Copyright (C) 1996 Elsevier Science Ltd
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页码:197 / 202
页数:6
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