title: YM155 induces apoptosis through proteasome-dependent degradation of MCL-1 in primary effusion lymphoma.
abstract: Primary effusion lymphoma (PEL) is a lymphoma that shows malignant effusion in body cavities without contiguous tumor masses and has a very poor prognosis. We recently developed a novel drug screening system using patient-derived xenograft (PDX) cells that maintained the primary cell phenotype better than cell lines. This screening is expected to discover anti-tumor drugs that have been overlooked by conventional screening using cell lines. We herein performed this screening to identify new therapeutic agents for PEL. We screened 3518 compounds with known pharmaceutical activities based on cytotoxic effects on PDX cells of PEL and selected YM155, a possible survivin inhibitor. It exerted strong anti-tumor effects in PDX cells and three cell lines of PEL; the GI50of YM155 was 1.2-7.9nM. We found that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein levels prior to decreasing survivin levels, and this was inhibited by a proteasome inhibitor. The knockdown of MCL-1 by siRNA induced cell death in a PEL cell line, suggesting the involvement of decreased MCL-1 levels in YM155-induced cell death. YM155 also induced the phosphorylation of ERK1/2 and MCL-1, and a MEK1 inhibitor inhibited the phosphorylation of ERK1/2, degradation of MCL-1, and YM155-induced apoptosis. These results indicate that YM155 induces the proteasome-dependent degradation of MCL-1 through its phosphorylation by ERK1/2 and causes apoptosis in PEL cells. Furthermore, a treatment with YM155 significantly inhibited the development of ascites in PEL PDX mice. These results suggest the potential of YM155 as an anti-cancer agent for PEL.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: bun-hy@med.nagoya-u.ac.jp.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Hematology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Morishita
authors.affiliation: Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan.
authors.forename: Keiki
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Minamikawa
authors.affiliation: Department of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Iwase
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Hirano
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Hematology, Ogaki Municipal Hospital, Gifu, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Imoto
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009285:Naphthoquinones; D046988:Proteasome Endopeptidase Complex; C523798:sepantronium
keywords: 6-BIO (PubChem CID: 11405589); Chicago sky blue 6B (PubChem CID: 9566045); Daunorubicin (PubChem CID: 62770); Drug screening; HIV; Idarubicin (PubChem CID: 636362); Licochalcone A (PubChem CID: 5318998); Mitoxantrone (PubChem CID: 51082); Patient-derived xenograft; Phorbol 12-myristate 13-acetate (PubChem CID: 27924); Primary effusion lymphoma; Pyurvinium pamoate (PubChem CID: 7847555); Tomatine (PubChem CID: 23760126); U0126 (PubChem CID: 5354033); Valproic Acid Sodium Salt (PubChem CID: 24277744); Verteporfin (PubChem CID: 5362420); YM155; YM155 (PubChem CID: 11178236); Z-VAD-FMK (PubChem CID: 5497174)