TY - JOUR
T1 - Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin
AU - Kuroda, Junya
AU - Kamitsuji, Yuri
AU - Kimura, Shinya
AU - Ashihara, Eishi
AU - Kawata, Eri
AU - Nakagawa, Yoko
AU - Takeuichi, Miki
AU - Murotani, Yoshihide
AU - Yokota, Asumi
AU - Tanaka, Ruriko
AU - Andreeff, Michael
AU - Taniwaki, Masafumi
AU - Maekawa, Taira
N1 - Funding Information:
Acknowledgments We are grateful to Professor T Nakahata (Kyoto University) and Drs. DCS Huang and LA O’Reilly (WEHI) for reagents, scientific advice, and technical support. This work was partly supported by Grants-in-Aid for Young Scientists from MEXT, the Kobayashi Foundation of Innovative Cancer Chemotherapy, and Japan Leukaemia Research Fund (to J.K.).
PY - 2008/6
Y1 - 2008/6
N2 - 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-FLIPL/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 β-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.
AB - 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-FLIPL/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 β-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.
KW - Apoptosis
KW - Homoharringtonine
KW - Mcl-1
KW - Multiple myeloma
KW - XIAP
KW - β-Catenin
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UR - http://www.scopus.com/inward/citedby.url?scp=46149088684&partnerID=8YFLogxK
U2 - 10.1007/s12185-008-0081-8
DO - 10.1007/s12185-008-0081-8
M3 - Article
C2 - 18415656
AN - SCOPUS:46149088684
SN - 0925-5710
VL - 87
SP - 507
EP - 515
JO - International journal of hematology
JF - International journal of hematology
IS - 5
ER -