title: Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-catenin.
abstract: Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan. junkuro@koto.kpu-m.ac.jp.
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.|Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kamitsuji
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.|Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Kawata
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Takeuichi
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Murotani
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Asumi
authors.initials: A
authors.lastname: Yokota
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Ruriko
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, M.D. Anderson Cancer Center, Unit 448, 1400 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000970:Antineoplastic Agents / Q000819:agonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006248:Harringtonines / Q000819:agonists / Q000494:pharmacology*; D000077863:Homoharringtonine; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011500:Protein Synthesis Inhibitors / Q000819:agonists / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis*; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D006248:Harringtonines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051176:beta Catenin; D000077863:Homoharringtonine