title: Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism.
abstract: Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Institute for Advanced Research, Nagoya University, Nagoya, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Mechanism of Aging, National Center for Geriatrics and Gerontology, Obu, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan.
authors.forename: Keiki
authors.initials: K
authors.lastname: Sugimoto
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: 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 Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Chisako
authors.initials: C
authors.lastname: Iriyama
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kuno
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomita
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
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; D017209:Apoptosis / Q000187:drug effects*; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018920:Coculture Techniques; D004640:Emetine / Q000494:pharmacology*; D015321:Gene Rearrangement / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D011500:Protein Synthesis Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D004640:Emetine
keywords: diffuse large B-cell lymphoma; emetine; glycolysis; high-throughput drug screening; microenvironment