Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells
Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells
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DOI：
10.1093/jn/131.6.1839
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发表时间：
2001-06-01
影响因子：
4.2
通讯作者：
Stein, J
中科院分区：
文献类型：
--
作者：
Gaschott, T;Steinhilber, D;Stein, J
三丁酸甘油酯是天然丁酸酯的前药，已经对其进行了评价，目的是克服天然丁酸酯作为药物的药代动力学缺点，即，其在肿瘤细胞中快速代谢且不能达到药理学浓度。我们研究了三丁酸甘油酯对人结肠癌细胞系Caco-2细胞生长、分化和维生素D受体表达的影响。三丁酸甘油酯比天然丁酸酯更有效地抑制生长和诱导细胞分化。加入生理浓度的二羟胆钙化醇[（OH）（2）D-3]后，该作用进一步增强。三丁酸甘油酯和（OH）（2）D-3在Caco-2细胞中的协同作用是由于三丁酸甘油酯诱导的维生素D受体的过表达，如通过逆转录酶-聚合酶链反应所测量的。用三丁酸甘油酯处理使（OH）（2）D-3与其受体的结合增加了1.5倍，而受体亲和力没有任何变化。我们的结论是，三丁酸甘油酯可能，至少部分地，发挥其生长减少和分化诱导作用的Caco-2细胞的上调维生素D受体，这可能提供了一个有用的治疗方法，在化学预防和治疗结直肠癌的两种营养素自然发生在人类饮食。
Tributyrin, a prodrug of natural butyrate, has been evaluated with an aim to overcome pharmacokinetic drawbacks of natural butyrate as a drug, i.e., its rapid metabolization and inability to achieve pharmacologic concentrations in neoplastic cells. We studied the effects of tributyrin on growth, differentiation and vitamin D receptor expression in Caco-2 cells, a human colon cancer cell line. Tributyrin was more potent in inhibiting growth and inducing cell differentiation than natural butyrate. The effect was further enhanced after addition of physiologic concentrations of dihydroxycholecalciferol [(OH)(2)D-3]. The synergistic effect of tributyrin and (OH)(2)D-3 in Caco-2 cells was due to tributyrin-induced overexpression of the vitamin D receptor, as measured by reverse transcriptase-polymerase chain reaction. Treatment with tributyrin increased binding of (OH)(2)D-3 to its receptor 1.5-fold, without any change in receptor affinity. We conclude that tributyrin may, at least in part, exert its growth-reducing and differentiation-inducing effect in Caco-2 cells by an upregulation of the vitamin D receptor, this may provide a useful therapeutic approach in chemoprevention and treatment of colorectal cancer by the two nutrients occurring naturally in human diet.