A 24-phenylsulfone analog of vitamin D inhibits 1α, 25-dihydroxyvitamin D3 degradation in vitamin D metabolism-competent cells
A 24-phenylsulfone analog of vitamin D inhibits 1α, 25-dihydroxyvitamin D3 degradation in vitamin D metabolism-competent cells
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DOI：
10.1124/jpet.106.115451
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Cross, Heide S.
中科院分区：
文献类型：
--
作者：
Lechner, Daniel;Manhardt, Teresa;Cross, Heide S.
抗有丝分裂、促分化和促凋亡的类固醇激素1 α，25-二羟维生素D-3 [1（α），25-（OH）（2）D-3]在超生理水平具有治疗肿瘤的潜力。然而，来自肿瘤易感器官如结肠、前列腺和乳腺的上皮细胞不仅表达维生素D受体，还表达维生素D羟化酶。与正常细胞相比，恶性细胞具有高基础水平的羟化酶25-羟基维生素D-3-24-羟化酶（CYP 24），此外，还具有诱导CYP 24响应1 α，25-（OH）（2）D-3的潜力。由于CYP 24的24-羟基化在治疗过程中会迅速降解类固醇激素，因此应抑制肿瘤细胞中的酶活性。我们证明，1 α，25-（OH）（2）D-3的24-苯砜类似物KRC-24 SO（2）Ph-1（S-4a）可快速有效地抑制来自结肠、前列腺和乳腺的人肿瘤细胞中的24-羟化酶活性。尽管酶抑制是直接相互作用的结果，但S-4a作为维生素D类似物，显然与维生素D受体结合并诱导CYP 24 mRNA，但这并不转化为酶活性增加。25-羟基维生素D-3-1 α-羟化酶的表达完全不受S-4a的影响。当1 α，25-（OH）（2）D-3和S-4a同时加入细胞培养物中时，CYP 24的转录增加，可能是由于激素半衰期增加。结肠细胞系COGA-13具有非常高水平的CYP 24，因此对维生素D的作用具有抗性。然而，S-4a赋予1 α，25-（OH）（2）D-3抗有丝分裂活性，因此可能构成刺激基于维生素D的抗肿瘤活性的抗增殖潜力的治疗剂。
The antimitotic, prodifferentiating, and proapoptotic steroid hormone, 1 alpha, 25-dihydroxyvitamin D-3 [1(alpha),25-(OH)(2)D-3], at supraphysiological levels has potential for tumor therapy. However, epithelial cells from tumor-prone organs such as colon, prostate, and breast express not only the vitamin D receptor, but also vitamin D hydroxylases. In contrast to normal cells, malignant cells have high basal levels of the hydroxylase 25- hydroxyvitamin D-3-24-hydroxylase (CYP24) and, in addition, have the potential to induce CYP24 in response to 1 alpha,25-(OH)(2)D-3. Because 24-hydroxylation by CYP24 would rapidly degrade the steroid hormone in the course of therapy, the enzyme activity in tumor cells should be inhibited. We demonstrate that a 24-phenylsulfone analog of 1 alpha,25-(OH)(2)D-3, KRC-24SO(2)Ph-1 (S-4a), rapidly and potently inhibits 24-hydroxylase activity in human tumor cells derived from colon, prostate, and mammary gland. Although enzymatic inhibition is a consequence of direct interaction, S-4a as a vitamin D analog apparently binds to the vitamin D receptor and induces CYP24 mRNA, which, however, is not translated into increased enzymatic activity. 25-Hydroxyvitamin D-3-1 alpha-hydroxylase expression is not affected at all by S-4a. When both 1 alpha,25-(OH)(2)D-3 and S-4a are added to the cell culture, transcription of CYP24 is increased, possibly because of an increase in the half-life of the hormone. The colon cell line COGA-13 has very high levels of CYP24 and is, therefore, resistant to the action of vitamin D. Yet, S-4a imparts antimitotic activity to 1 alpha,25-(OH)(2)D-3 and may therefore constitute a therapeutic to stimulate the antiproliferative potential of vitamin D-based antitumor activity.