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Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

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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-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.

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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.).

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan

    Junya Kuroda, Yuri Kamitsuji, Eri Kawata & Masafumi Taniwaki

  2. Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Yuri Kamitsuji, Shinya Kimura, Eishi Ashihara, Eri Kawata, Yoko Nakagawa, Miki Takeuichi, Yoshihide Murotani, Asumi Yokota, Ruriko Tanaka & Taira Maekawa

  3. 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

    Michael Andreeff

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  1. Junya Kuroda
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Correspondence to Junya Kuroda.

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Kuroda, J., Kamitsuji, Y., Kimura, S. et al. Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin. Int J Hematol 87, 507–515 (2008). https://doi.org/10.1007/s12185-008-0081-8

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