RRC ID 43831
Author Kimura K, Sakamoto Y, Fujisawa N, Uesugi S, Aburai N, Kawada M, Ohba S, Yamori T, Tsuchiya E, Koshino H.
Title Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants.
Journal Bioorg Med Chem
Abstract 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 IC(50) = 3.4 μM and induced apoptosis against the human promyelocytic leukemia cell line HL60 through a new stable rearrangement product (1) when in the presence of FeSO(4). 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 Fe(2+) 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 FeSO(4) 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 γ = 0.158). EDBD showed anti-tumor effects against a xenograft of Lox-IMVI cells in vivo.
Volume 20(12)
Pages 3887-97
Published 2012-6-15
DOI 10.1016/j.bmc.2012.04.025
PII S0968-0896(12)00300-8
PMID 22575162
MeSH Animals Antineoplastic Agents, Phytogenic / chemistry Antineoplastic Agents, Phytogenic / isolation & purification Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis / drug effects* Asteraceae / chemistry* Cell Proliferation / drug effects Dose-Response Relationship, Drug Drug Screening Assays, Antitumor HL-60 Cells Humans Mice Mice, Nude Neoplasms, Experimental / drug therapy* Neoplasms, Experimental / pathology Plants, Edible / chemistry* Sesquiterpenes / chemistry Sesquiterpenes / isolation & purification Sesquiterpenes / pharmacology* Structure-Activity Relationship
IF 2.802
Times Cited 23
WOS Category CHEMISTRY, MEDICINAL CHEMISTRY, ORGANIC BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells