title: YM155 suppresses cell proliferation and induces cell death in human adult T-cell leukemia/lymphoma cells.
abstract: Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of patients with aggressive ATL remains poor because ATL cells acquire resistance to conventional cytotoxic agents. Therefore, development of novel agents is urgently needed. We examined the effects of YM155, sepantronium bromide, on cell proliferation and survival of ATL or HTLV-1-infected T-cell lines, S1T, MT-1, and MT-2. We found that YM155 suppressed cell proliferation in these cells and induced cell death in S1T and MT-1 cells. Both real-time quantitative polymerase chain reaction and immunoblot analyses showed suppression of survivin expression in S1T, MT-1, and MT-2 cells. In addition, we observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase in YM155-treated S1T and MT-1 cells, indicating that YM155 induces caspase-dependent apoptosis in these cells. To clarify the mechanism of drug tolerance of MT-2 cells in terms of YM155-induced cell death, we examined intracellular signaling status in these cells. We found that STAT3, STAT5, and AKT were constitutively phosphorylated in MT-2 cells but not in S1T and MT-1 cells. Treatment with YM155 combined with the STAT3 inhibitor S3I-201 significantly suppressed cell proliferation compared to that with either YM155 or S3I-201 in MT-2 cells, indicating that STAT3 may play a role in tolerance of MT-2 cells to YM155 and that STAT3 may therefore be a therapeutic target for YM155-resistant ATL cells. These results suggest that YM155 presents potent antiproliferative and apoptotic effects via suppression of survivin in ATL cells in which STAT3 is not constitutively phosphorylated. YM155 merits further investigation as a potential chemotherapeutic agent for ATL.
authors.affiliation: Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Ryousei
authors.initials: R
authors.lastname: Sasaki
authors.affiliation: Department of Medical Oncology, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan. Electronic address: shigei@iwate-med.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ito
authors.affiliation: Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Asahi
authors.affiliation: Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ishida
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D015490:HTLV-I Infections / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000473:pathology*; D009285:Naphthoquinones / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D000077022:Survivin; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D000077022:Survivin; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; C523798:sepantronium
keywords: Adult T-cell leukemia; Mcl-1; STAT3; Surviving; YM155