mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether
mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether
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DOI：
10.1016/s0006-2952(02)01221-2
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发表时间：
2002-08-15
影响因子：
5.8
通讯作者：
Bauer, R
中科院分区：
文献类型：
--
作者：
Efferth, T;Olbrich, A;Bauer, R
抗疟青蒿素衍生物青蒿琥酯（ART）、蒿醚（ARE）和蒿醚（ARM）显示出显著的抗肿瘤活性。在本研究中，我们鉴定了与肿瘤细胞对ART、ARE和ARM反应相关的mRNA表达谱。我们对美国国家癌症研究所数据库中464个基因的抑制浓度50% （IC50）值与基础mRNA表达水平进行了相关性和分层聚类分析。相关ART的IC50值。ARE和ARM以及16种已确定的抗肿瘤药物显示，青蒿素衍生物不能与具有确定作用方式的已知类别药物分配。464个基因中有208个（45%）的基础mRNA表达与至少一种青蒿素衍生物的IC50值显著相关。这些基因来自不同的类别（耐药基因、DNA损伤与修复基因、细胞凋亡调节基因、增殖相关基因、致癌基因、肿瘤抑制基因和细胞因子）。我们通过层次聚类分析确定了两个不同的基因簇。一个簇主要包含与所有三种青蒿素衍生物显著相关的基因。这组重叠的基因指向了三种药物抑制肿瘤的共同分子机制，其中影响细胞增殖的基因可能发挥重要作用。第二簇包含与青蒿素衍生物对癌细胞的反应不同相关的基因。该簇中相关耐药基因数量按ART < ARE < ARM的顺序增加，且与3种药物的IC50值按同一顺序增加呈平行关系。与ARE和ARM相比，ART的活性更高，因此。可以解释为影响抗逆转录病毒治疗作用的耐药基因数量较少。目前的分析是对候选基因产生假设和更详细地解剖单个基因对肿瘤细胞中青蒿素衍生物活性的功能作用的起点。(C) 2002爱思唯尔科学有限公司版权所有。
The antimalarial artemisinin derivatives artesunate (ART), arteether (ARE), and artemether (ARM) reveal remarkable antineoplastic activity. In the present investigation, we identified mRNA expression profiles associated with the response of tumor cells to ART, ARE, and ARM. We performed correlation and hierarchical cluster analyses of inhibition concentration 50% (IC50) values and basal mRNA expression levels of 464 genes deposited in the database of the National Cancer Institute, USA. Correlating IC50 values of ART. ARE, and ARM and of 16 established antineoplastic drugs revealed that the artemisinin derivatives could not be assigned with a known class of drugs with defined mode(s) of action. The basal mRNA expression of 208 out of 464 genes (45%) correlated significantly with IC50 values of at least one artemisinin derivative. These genes were from different classes (drug resistance genes, DNA damage and repair genes, apoptosis-regulating genes, proliferation-associated genes, oncogenes, tumor suppressor genes and cytokines). We identified two different gene clusters by hierarchical cluster analysis. One cluster contained predominately genes significantly correlated to all three artemisinin derivatives. This overlapping set of genes points to common molecular mechanisms of tumor inhibition by all three drugs in which genes affecting cellular proliferation may play an important role. The second cluster contained genes differentially associated with the response of artemisinin derivatives to cancer cells. The number of correlating drug resistance genes in this cluster increased in the order ART < ARE < ARM and was paralleled by increasing IC50 values of the three drugs in the same order. The higher activity of ART in comparison to ARE and ARM may, thus. be explained by a lower number of drug resistance genes affecting ARTS action. The present analysis is a starting point for the generation of hypotheses on candidate genes and for a more detailed dissection of the functional role of individual genes for the activity of artemisinin derivatives in tumor cells. (C) 2002 Elsevier Science Inc. All rights reserved.