CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells
CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells
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DOI：
10.3748/wjg.v19.i17.2621
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发表时间：
2013-05-07
影响因子：
4.3
通讯作者：
Lakatos, Peter
中科院分区：
文献类型：
--
作者：
Kosa, Janos P.;Horvath, Peter;Lakatos, Peter
目的：研究了维生素D3对包括结直肠癌（CRC）在内的多种肿瘤的作用。25-羟基维生素D3-24-羟化酶（CYP24A1）是一种使活性维生素D3代谢物1,25-二羟基维生素D3 （1,25-D3）失活的酶，被认为是决定1,25-D3生物半衰期的主要酶。在结直肠癌发生过程中，CYP24A1的表达和浓度显著升高，提示这一现象可能是1,25- d3治疗结直肠癌疗效的原因。本研究旨在探讨维生素D3在抑制CYP24A1细胞色素P450组分活性后对人CRC细胞系Caco-2的抗肿瘤作用。方法：检测CYP24A1 mRNA的表达及1,25- d3对Caco-2细胞株抑制CYP24A1后的影响。分别采用磺胺- B染色法和溴脱氧尿苷法测定细胞活力和增殖，通过细胞培养上清乳酸脱氢酶含量测定细胞毒性。实时逆转录聚合酶链反应检测CYP24A1表达。合成了一些四酮类化合物，研究了它们对CP24A1的抑制活性。结果：在1,25- d3的作用下，CYP24A1 mRNA的表达显著增强，且呈时间和剂量依赖性。Caco-2细胞的活力和增殖不受单独给药1,25- d3的影响，但同时给药1,25- d3和KD-35（一种抑制cyp24a1的四酮）可显著降低Caco-2细胞的活力和增殖。我们的数据表明，共同施用KD-35和1,25- d3的作用机制不涉及直接的细胞毒性作用，而是抑制细胞增殖。结论：KD-35等化合物选择性抑制CYP24A1可能是增强1,25- d3对结直肠癌抗肿瘤作用的新途径。(三)2013年白石登。版权所有。
AIM: The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological halflife of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity.METHODS: We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine- B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by realtime reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity.RESULTS: In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by coadministration of 1,25-D3 and KD-35, a CYP24A1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation.CONCLUSION: These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC. (C) 2013 Baishideng. All rights reserved.