Molecular modes of action of artesunate in tumor cell lines
Molecular modes of action of artesunate in tumor cell lines
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DOI：
10.1124/mol.64.2.382
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发表时间：
2003-08-01
影响因子：
3.6
通讯作者：
Funk, JO
中科院分区：
文献类型：
--
作者：
Efferth, T;Sauerbrey, A;Funk, JO
抗疟药青蒿琥酯（ART）对55种美国癌细胞系有显著的细胞毒作用。S.国家癌症研究所（NCI）。ART的50%抑制浓度（IC 50值）与细胞倍增时间（P = 0.00132）和处于G（0）/G（1）（P = 0.02244）或S期（P = 0.03567）的细胞比例显著相关。我们从NCI数据库中选择了通过微阵列杂交获得的465个基因的mRNA表达数据。这些基因属于不同的生物学类别（耐药性基因、DNA损伤反应和修复基因、癌基因和肿瘤抑制基因、肿瘤坏死调节基因、增殖相关基因、以及细胞因子和嘌呤相关基因）。465个基因中有54个（= 12%）的组成型表达与ART的IC 50值显著相关。对这12个基因进行分层聚类分析，可以区分ART敏感或ART耐药细胞系的聚类（P = 0.00017）。为了示例性验证，使用用12个基因中的3个转导的细胞系来证明因果关系。缺失突变的表皮生长因子受体（EGFR）和γ-谷氨酰半胱氨酸合成酶的cDNA增加了对ART的抗性。使用四环素阻遏物表达载体的CDC 25 A基因的条件表达增加了对ART的敏感性。差异表达MDR 1、MRP 1、ART通过p53依赖和非依赖途径作用于同基因型p53 +/+ p21（WAF 1/CIP 1）+/+、p53 -/- p21（WAF 1/CIP 1）+/ +和p53 +/ + p21（WAF 1/CIP 1）-/-结肠癌细胞。
A profound cytotoxic action of the antimalarial, artesunate ( ART), was identified against 55 cancer cell lines of the U. S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC50 values) for ART correlated significantly to the cell doubling times ( P = 0.00132) and the portion of cells in the G(0)/G(1) (P = 0.02244) or S cell cycle phases ( P = 0.03567). We selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data base. These genes belong to different biological categories ( drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (= 12%) genes correlated significantly to the IC50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines ( P = 0.00017). For exemplary validation, cell lines transduced with 3 of the 12 genes were used to prove a causative relationship. The cDNAs for a deletion-mutated epidermal growth factor receptor ( EGFR) and for gamma-glutamylcysteine synthetase increased resistance to ART. The conditional expression of the CDC25A gene using a tetracycline repressor expression vector increased sensitivity toward ART. Multidrug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent and-independent pathways in isogenic p53 +/+ p21(WAF1/CIP1)+/+, p53 -/- p21(WAF1/CIP1) +/ +, and p53 +/ + p21(WAF1/CIP1) -/- colon carcinoma cells.