Comparative effects of 1,25(OH)(2)D-3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells
Comparative effects of 1,25(OH)(2)D-3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells
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DOI：
10.1023/a:1005772432465
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发表时间：
1997-01-01
影响因子：
3.8
通讯作者：
Welsh, J
中科院分区：
文献类型：
--
作者：
SimboliCampbell, M;Narvaez, CJ;Welsh, J
1，25-二羟维生素D-3 [1，25（OH）（2）D-3]是维生素D的活性代谢物，在体内和体外均抑制乳腺癌细胞生长。除了其抗增殖作用外，1，25（OH）（2）D-3还诱导MCF-7细胞凋亡的形态学和生化标志物。在本文报道的研究中，我们比较了1，25（OH）（2）D-3和EB 1089（一种低钙维生素D类似物）对MCF-7细胞的细胞周期动力学和凋亡的影响。两种维生素D化合物均以时间和剂量依赖性方式减少活MCF-7细胞数量，其中EB 1089的效力比1，25（OH）（2）D-3高约50倍。流式细胞术分析表明，这两种药物诱导细胞周期停滞在G（0）/G（1），这与视网膜母细胞瘤（Rb）蛋白的低磷酸化形式的积累。1，25（OH）（2）D-3或EB 1089处理MCF-7细胞48 h后，出现细胞质浓缩、核固缩、染色质浓缩和DNA断裂等凋亡特征。用任何一种药物处理的细胞表现出与乳腺退化相关的蛋白质（簇蛋白和组织蛋白酶B）的上调和抗凋亡蛋白bcl-2的下调。这些研究表明，尽管维生素D类似物EB 1089在体内具有较低的钙离子活性，但其诱导的作用与1，25（OH）（2）D-3在体外对MCF-7细胞的细胞数量、细胞周期和凋亡指数的作用不可区分。此外，由于这两种药物迅速下调雌激素受体，雌激素依赖性信号传导的破坏可能在MCF-7细胞中维生素D化合物诱导细胞凋亡中发挥作用。
1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], the active metabolite of vitamin D, inhibits breast cancer cell growth both in vivo and in vitro. In addition to its anti-proliferative effects, 1,25(OH)(2)D-3 induces morphological and biochemical markers of apoptosis in MCF-7 cells. In the studies reported here, we compared the effects of 1,25(OH)(2)D-3 and EB1089, a low calcemic vitamin D analog, on cell cycle kinetics and apoptosis in MCF-7 cells. Both vitamin D compounds reduced viable MCF-7 cell number in a time and dose dependent manner, with EB1089 approximately 50 fold more potent than 1,25(OH)(2)D-3. Flow cytometric analysis indicated that both agents induced cell cycle arrest in G(0)/G(1) which was associated with accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein. MCF-7 cells treated with either 1,25(OH)(2)D-3 or EB1089 for 48 h exhibited characteristics of apoptosis, including cytoplasmic condensation, pyknotic nuclei, condensed chromatin and DNA fragmentation. Cells treated with either agent exhibited up regulation of proteins associated with mammary gland regression (clusterin and cathepsin B) and down regulation of the anti-apoptotic protein bcl-2. These studies demonstrate that, despite its lower calcemic activity in vivo, the vitamin D analog EB1089 induces effects that are indistinguishable from those of 1,25(OH)(2)D-3 on cell number, cell cycle and indices of apoptosis in MCF-7 cells in vitro. In addition, since both agents rapidly down regulate estrogen receptor, disruption of estrogen dependent signalling may play a role in the induction of apoptosis by vitamin D compounds in MCF-7 cells.