Danielsson C, Mathiasen I S, James S Y, Nayeri S, Bretting C, Hansen C M, Colston K W, Carlberg C
Clinique de Dermatologie, Hôpital Cantonal Universitaire, Genève, Switzerland.
J Cell Biochem. 1997 Sep 15;66(4):552-62. doi: 10.1002/(sici)1097-4644(19970915)66:4<552::aid-jcb14>3.0.co;2-d.
The biologically active form of vitamin D3, the nuclear hormone 1 alpha,25-dihydroxyvitamin D3 (VD), is an important regulator of cellular growth, differentiation, and death. The hormone mediates its action through the activation of the transcription factor VDR, which is a member of the superfamily of nuclear receptors. In most cases the ligand-activated VDR is found in complex with the retinoid X receptor (RXR) and stimulates gene transcription mainly from VD response elements (VDREs) that are formed by two hexameric core binding motifs and are arranged either as a direct repeat spaced by three nucleotides (DR3) or as an inverted palindrome spaced by nine nucleotides (1P9). The two VD analogues CB1093 and EB1089 are both very potent inhibitors of the proliferation of MCF-7 cultured breast cancer cells displaying approximately 100-fold lower IC50 values (0.1 nM) than the natural hormone. In addition, CB1093 is even more potent in vivo than EB1089 in producing regression of experimental mammary tumors. Moreover, both VD analogues induce apoptosis in MCF-7 cells, but CB1093 is effective at concentrations approximately 10-fold lower than EB1089. In accordance, the reduction of Bcl-2 protein expression showed CB1093 to be more potent than EB1089. This suggests that the antiproliferative effect of CB1093 may be related mainly to its apoptosis inducing effect, whereas EB1089 may preferentially have effects on growth arrest. EB1089 is known to result in a selectivity for the activation of IP9-type VDREs, whereas CB1093 shows a preference for the activation of DR3-type VDREs. This promoter selectivity suggests that the effects of VD and its analogues on growth arrest and the induction of apoptosis may be mediated by different primary VD responding genes. In conclusion, CB1093 was found to be a potent inhibitor of rat mammary tumor growth in vivo. CB1093 also displayed a high potency in vitro in the induction of apoptosis, a process that may be linked to a promoter selectivity for DR3-type VDREs.
维生素D3的生物活性形式，即核激素1α，25 - 二羟基维生素D3（VD），是细胞生长、分化和死亡的重要调节因子。该激素通过激活转录因子VDR来介导其作用，VDR是核受体超家族的成员。在大多数情况下，配体激活的VDR与视黄酸X受体（RXR）形成复合物，并主要从由两个六聚体核心结合基序形成的VD反应元件（VDRE）刺激基因转录，这些元件以三个核苷酸间隔的直接重复序列（DR3）或九个核苷酸间隔的反向回文序列（1P9）排列。两种VD类似物CB1093和EB1089都是MCF - 7培养的乳腺癌细胞增殖的非常有效的抑制剂，其IC50值（0.1 nM）比天然激素低约100倍。此外，在使实验性乳腺肿瘤消退方面，CB1093在体内比EB1089更有效。而且，两种VD类似物都能诱导MCF - 7细胞凋亡，但CB1093在比EB1089低约10倍的浓度下就有效。相应地，Bcl - 2蛋白表达的降低表明CB1093比EB1089更有效。这表明CB1093的抗增殖作用可能主要与其诱导凋亡的作用有关，而EB1089可能优先对生长停滞有影响。已知EB1089会导致对IP9型VDRE激活的选择性，而CB1093则表现出对DR3型VDRE激活的偏好。这种启动子选择性表明VD及其类似物对生长停滞和凋亡诱导的作用可能由不同的主要VD反应基因介导。总之，发现CB1093是体内大鼠乳腺肿瘤生长的有效抑制剂。CB1093在体外诱导凋亡方面也表现出高效能，这一过程可能与对DR3型VDRE的启动子选择性有关。
