2-Methoxyestardiol and bortezomib/proteasome-inhibitor overcome dexamethasone-resistance in multiple myeloma cells by modulating Heat Shock Protein-27

Apoptosis. 2004 Mar;9(2):149-55. doi: 10.1023/B:APPT.0000018797.66067.6c.


Multiple myeloma (MM) remains fatal despite all available therapies. Initial treatment with conventional drugs such as, Dexamethasone (Dex) effectively induces MM cell death; however, prolonged drug exposures results in the development of chemoresistance. Our prior study demonstrated that 2-Methoxyestradiol (2ME2) induces apoptosis in multiple myeloma (MM) cells resistant to Dexamethasone (Dex). Here, we show the mechanism whereby 2ME2 overcomes Dex-resistance. The oligonucleotide array analysis demonstrates that Heat Shock Protein-27 (Hsp27) is upregulated in Dex-resistant, but not in Dex-sensitive MM cells. Proteomics analysis of Hsp27-immunocomplexes revealed the presence of actin in Dex-resistant, but not in Dex-sensitive cells. Biochemical interaction between Hsp27 and actin was examined by co-immunoprecipitation with anti-Hsp27 or actin Abs. Far western blot analysis using GST-Hsp27 fusion protein showed a direct association with actin both in vitro and in vivo. Importantly, 2ME2- or Bortezomib/Proteasome inhibitor (PS-341)-induced apoptosis in Dex-resistant MM cell lines and MM patient cells is associated with disruption of the Hsp27-actin complexes. Finally, blockade of Hsp27 by anti-sense strategy enhanced anti-MM activity of both 2ME2 and PS-341. These findings provide the clinical application of novel therapeutics targeting Hsp27 to improve patient outcome in MM.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2-Methoxyestradiol
  • Actins / metabolism
  • Antineoplastic Agents / pharmacology*
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Dexamethasone*
  • Drug Resistance, Neoplasm*
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Multiple Myeloma / metabolism*
  • Peptides / chemistry
  • Proteasome Inhibitors*
  • Pyrazines / pharmacology*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • Actins
  • Antineoplastic Agents
  • Boronic Acids
  • Heat-Shock Proteins
  • Peptides
  • Proteasome Inhibitors
  • Pyrazines
  • Estradiol
  • Bortezomib
  • 2-Methoxyestradiol
  • Dexamethasone