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

Int J Hematol. 2008 Jun;87(5):507-515. doi: 10.1007/s12185-008-0081-8. Epub 2008 Apr 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / agonists
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Harringtonines / agonists
  • Harringtonines / pharmacology*
  • Homoharringtonine
  • Humans
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism*
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Synthesis Inhibitors / agonists
  • Protein Synthesis Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • X-Linked Inhibitor of Apoptosis Protein / biosynthesis*
  • beta Catenin / biosynthesis*


  • Antineoplastic Agents
  • Harringtonines
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Synthesis Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • beta Catenin
  • Homoharringtonine