title: OSU-A9, an indole-3-carbinol derivative, induces cytotoxicity in acute myeloid leukemia through reactive oxygen species-mediated apoptosis.
abstract: Indole-3-carbinol (I3C) is a broadly targeted phytochemical shown to prevent carcinogenesis in animal studies and to suppress the proliferation of cancer cells of human breast, colon, prostate, and endometrium. Here we demonstrate that OSU-A9, an I3C derivative with improved anticancer potency, induces cytotoxicity in acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells were less sensitive to OSU-A9 than leukemia cells. OSU-A9 induces caspase activation, PARP cleavage, and autophagy but not autophagic cell death. Interestingly, pretreatment of AML cell lines and primary AML cells with N-acetylcysteine or glutathione rescues them from apoptosis (and concomitant PARP cleavage) and Akt hypophosphorylation, implicating a key role of reactive oxygen species (ROS) in OSU-A9-related cytotoxicity. Importantly, the anticancer utility of OSU-A9 is extended in vivo as it, administered intraperitoneally, suppresses the growth of THP-1 xenograft tumors in athymic nude mice without obvious toxicity. This study shows that ROS-mediated apoptosis contributes to the anticancer activity of OSU-A9 in AML cell lines and primary AML cells, and thus should be considered in the future assessment of its translational value in AML therapy.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, 2, Yude road, Taichung 40402 Taiwan; College of Medicine, School of Medicine, China Medical University, 91, Hsueh-Shih road, Taichung 40402 Taiwan. Electronic address: lybai6@gmail.com.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Bai
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Chiu
authors.forename: Chia-Yung
authors.initials: CY
authors.lastname: Wu
authors.forename: Su-Peng
authors.initials: SP
authors.lastname: Yeh
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Sargeant
authors.forename: Po-Han
authors.initials: PH
authors.lastname: Lin
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Liao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000432:Methanol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C523234:(1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl)-methanol; D000970:Antineoplastic Agents; D019925:Cyclin A; D056744:Cyclin B1; D007211:Indoles; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D000432:Methanol
keywords: Acute myeloid leukemia; Glutathione; Indole-3-carbinol; OSU-A9; Reactive oxygen species