title: Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants.
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.
authors.affiliation: Department of Biological Chemistry and Food Science, Iwate University, Morioka 020-8550, Japan. kimurak@iwate-u.ac.jp
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kimura
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Nozomi
authors.initials: N
authors.lastname: Fujisawa
authors.forename: Shota
authors.initials: S
authors.lastname: Uesugi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Aburai
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawada
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Ohba
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Eiko
authors.initials: E
authors.lastname: Tsuchiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshino
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019659:Asteraceae / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010945:Plants, Edible / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C576517:3,6-epidioxy-1,10-bisaboladiene; D000972:Antineoplastic Agents, Phytogenic; D012717:Sesquiterpenes