title: Furanonaphthoquinones cause apoptosis of cancer cells by inducing the production of reactive oxygen species by the mitochondrial voltage-dependent anion channel.
abstract: The mitochondrial production of reactive oxygen species has been implicated in the anticancer activity of furanonaphthoquinone. However, the mechanism of the activation remains elusive. In the current study, we found that treatment of HeLa cells with 2-methyl-5(or -8)-hydroxy-furanonaphthoquinone (FNQ13) induces mitochondrial swelling, followed by apoptosis. This toxic effect of FNQ13 was reduced by the radical scavengers alpha-tocopherol and trolox. Cytochemical experiments in isolated mitochondria showed that a combination of FNQ13 and NADH induces the production of H(2)O(2) at the exterior mitochondrial membrane surface. This production of H(2)O(2) was reduced by an antibody to the voltage-dependent anion channel (VDAC). Overexpression of the VDAC by transfection with vdac1 cDNA increased the production of H(2)O(2) by HeLa cells, whereas transfection with a small interfering RNA to VDAC reduced FNQ13-induced H(2)O(2) production and cell death due to an almost complete knockdown of VDAC expression. We also found significant correlations between the expression of VDAC and the induction of H(2)O(2) production and cell death by FNQ13 in 11 human cancer cell lines. These results indicate that the anticancer activity of furanonaphthoquinones depends on the production of reactive oxygen species by mitochondrial permeability transition pores including the VDAC.
authors.affiliation: Molecular and Cell Structural Science, Kanazawa Medical University, Uchinada, Ishikawa, Japan. simamura@kanazawa-med.ac.jp <simamura@kanazawa-med.ac.jp>
authors.forename: Eriko
authors.initials: E
authors.lastname: Simamura
authors.forename: Kei-Ichi
authors.initials: K
authors.lastname: Hirai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimada
authors.forename: Junko
authors.initials: J
authors.lastname: Koyama
authors.forename: Yukie
authors.initials: Y
authors.lastname: Niwa
authors.forename: Shigeomi
authors.initials: S
authors.lastname: Shimizu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D006367:HeLa Cells / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009285:Naphthoquinones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C111775:2-methyl-8-hydroxynaphtho(2,3-b)furan-4,9-dione; D000970:Antineoplastic Agents; D007473:Ion Channels; D009285:Naphthoquinones; D017382:Reactive Oxygen Species