title: Delphinidin induces cytotoxicity and potentiates cytocidal effect in combination with arsenite in an acute promyelocytic leukemia NB4 cell line.
abstract: The effects of delphinidin were investigated by focusing on growth inhibition, cell cycle arrest and apoptosis induction in the human acute promyelocytic leukemia (APL) NB4 cell line. Delphinidin exhibited a dose- and time-dependent cytotoxic effect against NB4 cells. Almost no cell cycle arrest, but an apparent increase in the percentage of sub-G1 cells was observed in delphinidin-treated cells. The activation of caspase-8 and -9 was observed as early as 1-h post-exposure to delphinidin, followed by the activation of caspase-3 from 3-h post-exposure. A substantial decrease in the expression level of Bid was also observed as early as 1-h post-exposure. A modest decrease in the mitochondrial membrane potential (ΔΨm) was observed at 3-h post-exposure, followed by a substantial time-dependent decrease in ΔΨm in treated cells. Delphinidin exerted more potent cytotoxicity against NB4 cells than normal peripheral blood mononuclear cells (PBMNCs). In addition, delphinidin in combination with an arsenic derivative arsenite (As(III)), which has demonstrated marked efficacy in patients with APL, achieved an enhanced cytocidal effect against NB4 cells, but lesser on PBMNCs. Treatment of NB4 cells with As(III) plus delphinidin did not increase, but decreased slightly, intracellular arsenic accumulation (As[i]) as compared to that treated with As(III) alone. These results suggested that delphinidin selectively sensitized NB4 cells to As(III), resulting in the enhancement of As(III) cytotoxicity by strengthening intrinsic/extrinsic pathway-mediated apoptosis induction, rather than affecting the As[i] levels. These observations may offer a rationale for the use of delphinidin to improve the clinical efficacy of As(III).
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Okusumi
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yoshino
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Moriyama
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Takagi
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Toyoda
mesh_terms: D000872:Anthocyanins / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects
chemical_list: D000872:Anthocyanins; D000970:Antineoplastic Agents; D018053:Arsenites; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; C017185:delphinidin; C015001:arsenite