title: Indirubin 3'-Epoxide Induces Caspase-Independent Cell Death in Human Neuroblastoma.
abstract: Indirubin inhibits cyclin-dependent kinases by binding to their ATP-binding site, thereby exerting potent cytotoxicity on some tumor cells. We examined the anti-tumor effect of indirubin 3'-epoxide on human neuroblastoma cell lines (IMR-32, SK-N-SH, and NB-39). The results revealed potent cytotoxicity of indirubin 3'-epoxide against the IMR-32 (IC50: 0.16 µM) and SK-N-SH (IC50: 0.07 µM) cells. Furthermore, it also induced an increase of the sub-G1 population in the IMR-32 cells. Examination by Hoechst 33342 staining revealed apoptosis characterized by cell shrinkage, nuclear condensation and nuclear fragmentation in a concentration-dependent manner. Furthermore, annexin V-propidium iodide (PI) double-staining revealed an increase in the percentage of early apoptotic cells following treatment of the cells with indirubin 3'-epoxide without activation of caspases. In addition, significant decreases in the protein level of survivin and poly(ADP-ribose)polymerase (PARP), and increase in that of apoptosis-inducing factor (AIF) were found in the nuclei of the cells. These results suggest that indirubin 3'-epoxide induced caspase-independent apoptosis through mechanisms involving DNA fragmentation and inhibition of DNA repair.
authors.affiliation: School of Pharmacy, Nihon University.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hanada
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Ichimaru
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Saito
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Satoru
authors.initials: S
authors.lastname: Asami
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyairi
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009447:Neuroblastoma / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D007211:Indoles; C000613731:indirubin 3'-epoxide; D020169:Caspases