Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants

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• 作者：Ken-ichi Kimura^a ; ^&dagger ; ; ^{kimurak@iwate-u.ac.jp} ; Yoshimi Sakamoto^a ; ^&dagger ; ; Nozomi Fujisawa^a ; Shota Uesugi^a ; Nobuhiro Aburai^a ; Manabu Kawada^b ; Shun-ichi Ohba^b ; Takao Yamori^c ; Eiko Tsuchiya^d ; Hiroyuki Koshino^e
• 关键词：EDBD ; 3 ; 6-epidioxy-1 ; 10-bisaboladiene ; ART ; artemisinin ; DHA ; dihydroartemisinin ; DFOM ; deferoxamine mesylate ; 纬 ; correlation coefficient on COMPARE Analysis ; PDA ; Photo Diode Array ; MAPK ; mitogen-activated protein kinase ; CDDP ; cis-diamminedichloroplati
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 June, 2012
• 卷：20
• 期：12
• 页码：3887-3897
• 文件大小：1472 K

摘要

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 rad9螖). It showed cytotoxicity at IC₅₀ = 3.4 渭M 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鈥?7鈥?dichlorofluorescin diacetate) assay. The in vitro reaction of EDBD with FeSO₄ also 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 纬 = 0.158). EDBD showed anti-tumor effects against a xenograft of Lox-IMVI cells in vivo.