Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants
Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants
复制标题
食用野生植物3,6-环氧-1,10-双没药二烯的裂解机制及抗肿瘤活性
DOI：
10.1016/j.bmc.2012.04.025
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Koshino H
中科院分区：
文献类型：
--
作者：
Kimura KI;Sakamoto Y;Fujisawa N;Uesugi S;Aburai N;Kawada M;Ohba SI;Yamori T;Tsuchiya E;Koshino H
利用突变酵母（cdc2-1 rad9Δ）从日本北部可食野生植物delphiniifolia和Cacalia hastata中分离到一种双aboladiene倍半萜内过氧化物化合物3,6-附二氧基-1,10-双aboladiene （EDBD）。在IC50=3.4μM时显示细胞毒性，并在FeSO4存在下通过一种新的稳定重排产物(1)诱导人早幼粒细胞白血病HL60细胞凋亡。这种转化机制不同于另一种倍半萜内过氧化物内酯化合物——双氢青蒿素（DHA），后者是一种抗疟疾药物。在铁离子螯合药物甲磺酸去铁胺（DFOM）的作用下，EDBD的细胞毒性下降，提示Fe2+引起的药物结构变化可能是其生物活性的原因。EDBD通过磷酸化p38丝裂原活化蛋白激酶（MAPK）诱导HL60细胞凋亡，并通过Western blot检测。通过DCFH-DA（2′，7′-二氯荧光素双乙酸酯）测定，EDBD可立即增加HL60细胞的DCF荧光强度。EDBD与feso4的体外反应也使DCF荧光强度呈剂量依赖性增加。这些结果表明，EDBD的生物活性涉及一个不稳定的碳中心自由基中间体。EDBD与DHA的JFCR39指纹图谱不存在相似性（相关系数γ=0.158）。EDBD在体内对异种Lox-IMVI细胞有抗肿瘤作用。
A bisabolane sesquiterpene endoperoxide compound, 3,6-epidioxy-1,10-bisaboladiene (EDBD), was isolated from edible wild plants grown in the northern area of Japan, Cacalia delphiniifolia and Cacalia hastata, using a mutant yeast (cdc2-1 rad9Δ). It showed cytotoxicity at IC50=3.4μM and induced apoptosis against the human promyelocytic leukemia cell line HL60 through a new stable rearrangement product (1) when in the presence of FeSO4. This conversion mechanism is different from another sesquiterpene endoperoxide lactone compound, dihydroartemisinin (DHA), which is an anti-malarial drug. The cytotoxicity of EDBD decreased in the presence of the ferrous ion chelating drug deferoxamine mesylate (DFOM), and this suggested that the structural change of the drug caused by Fe2+may be responsible for its biological activities. EDBD induced apoptosis via phosphorylation of p38 mitogen-activated protein kinase (MAPK) in HL60 cells, and was detected by Western blot. EDBD resulted in an immediate increase in DCF fluorescence intensity in HL60 cells using DCFH-DA (2′,7′-dichlorofluorescin diacetate) assay. The in vitro reaction of EDBD with FeSO4also increased DCF fluorescence intensity in a dose dependent manner. These results showed that the biological activity of EDBD involves an unstable carbon-centered radical intermediate. Furthermore, there was no similarity between the JFCR39 fingerprints of EDBD and DHA (correlation coefficient on COMPARE Analysis γ=0.158). EDBD showed anti-tumor effects against a xenograft of Lox-IMVI cells in vivo.