Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-catenin.
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.
Kuroda
Junya
J
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.
Kamitsuji
Yuri
Y
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.
Kimura
Shinya
S
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Ashihara
Eishi
E
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Kawata
Eri
E
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.
Nakagawa
Yoko
Y
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Takeuichi
Miki
M
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Murotani
Yoshihide
Y
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Yokota
Asumi
A
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Tanaka
Ruriko
R
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Andreeff
Michael
M
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.
Taniwaki
Masafumi
M
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
Maekawa
Taira
T
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
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*
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