Perspectives of differentiation therapies of acute myeloid leukemia: the search for the molecular basis of patients' variable responses to 1,25-dihydroxyvitamin d and vitamin d analogs.
Perspectives of differentiation therapies of acute myeloid leukemia: the search for the molecular basis of patients' variable responses to 1,25-dihydroxyvitamin d and vitamin d analogs.
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DOI：
10.3389/fonc.2014.00125
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发表时间：
2014
影响因子：
4.7
通讯作者：
Marcinkowska E
中科院分区：
文献类型：
--
作者：
Marchwicka A;Cebrat M;Sampath P;Snieżewski L;Marcinkowska E
肿瘤的分化治疗的概念大约有40年的历史。尽管在实验室中获得了许多令人鼓舞的结果，在体外和体内研究中，分化治疗的唯一真正成功的临床应用是基于全反式维甲酸（ATRA）的急性早幼粒细胞白血病（APL）的治疗。全反式维甲酸（ATRA）诱导APL白血病原始细胞向粒细胞分化，使APL的治疗从致命性转变为可治愈性。然而，全反式维甲酸不适用于其他急性髓性白血病（AML）。由于1，25-二羟基维生素D3（1，25 D）能够诱导白血病细胞的单核细胞分化，因此用维生素D类似物（VDA）治疗其他AML的想法被广泛接受。此外，某些类型的实体癌对体外应用的VDA有反应，因此推测VDA可用于许多临床应用。然而，早期的临床试验中，癌症患者接受1，25 D或VDA治疗，并没有得出结论性的结果。为了寻找AML患者对VDA的这种不可预测的反应的分子基础，我们使用患者的母细胞进行了离体实验。本实验还利用1，25 D-反应性和1，25 D-非反应性细胞系进行了实验，以研究它们对1，25 D诱导分化的抗性机制。我们发现，一个可能的原因可能是由于维生素D受体（VDR）mRNA在抗性细胞中的表达水平很低，这可以通过将细胞暴露于ATRA来增加。本文就VDR低表达的分子机制及ATRA对其表达的调控作一综述。
The concept of differentiation therapy of cancer is ~40 years old. Despite many encouraging results obtained in laboratories, both in vitro and in vivo studies, the only really successful clinical application of differentiation therapy was all-trans-retinoic acid (ATRA)-based therapy of acute promyelocytic leukemia (APL). ATRA, which induces granulocytic differentiation of APL leukemic blasts, has revolutionized the therapy of this disease by converting it from a fatal to a curable one. However, ATRA does not work for other acute myeloid leukemias (AMLs). Since 1,25-dihydroxyvitamin D3 (1,25D) is capable of inducing monocytic differentiation of leukemic cells, the idea of treating other AMLs with vitamin D analogs (VDAs) was widely accepted. Also, some types of solid cancers responded to in vitro applied VDAs, and hence it was postulated that VDAs can be used in many clinical applications. However, early clinical trials in which cancer patients were treated either with 1,25D or with VDAs, did not lead to conclusive results. In order to search for a molecular basis of such unpredictable responses of AML patients toward VDAs, we performed ex vivo experiments using patient’s blast cells. Experiments were also performed using 1,25D-responsive and 1,25D-non-responsive cell lines, to study their mechanisms of resistance toward 1,25D-induced differentiation. We found that one of the possible reasons might be due to a very low expression level of vitamin D receptor (VDR) mRNA in resistant cells, which can be increased by exposing the cells to ATRA. Our considerations concerning the molecular mechanism behind the low VDR expression and its regulation by ATRA are reported in this paper.