A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells

Cancer Res. 2005 Sep 15;65(18):8350-8. doi: 10.1158/0008-5472.CAN-05-0163.


Human multiple myeloma is a presently incurable hematologic malignancy, and novel biologically based therapies are urgently needed. GCS-100 is a polysaccharide derived from citrus pectin in clinical development for the treatment of cancer. Here we show that GCS-100 induces apoptosis in various multiple myeloma cell lines, including those resistant to dexamethasone, melphalan, or doxorubicin. Examination of purified patient multiple myeloma cells showed similar results. Specifically, GCS-100 decreases viability of bortezomib/PS-341-resistant multiple myeloma patient cells. Importantly, GCS-100 inhibits multiple myeloma cell growth induced by adhesion to bone marrow stromal cells; overcome the growth advantage conferred by antiapoptotic protein Bcl-2, heat shock protein-27, and nuclear factor-kappaB; and blocks vascular endothelial growth factor-induced migration of multiple myeloma cells. GCS-100-induced apoptosis is associated with activation of caspase-8 and caspase-3 followed by proteolytic cleavage of poly(ADP-ribose) polymerase enzyme. Combined with dexamethasone, GCS-100 induces additive anti-multiple myeloma cytotoxicity associated with mitochondrial apoptotic signaling via release of cytochrome c and Smac followed by activation of caspase-3. Moreover, GCS-100 + dexamethasone-induced apoptosis in multiple myeloma cells is accompanied by a marked inhibition of an antiapoptotic protein Galectin-3, without significant alteration in Bcl-2 expression. Collectively, these findings provide the framework for clinical evaluation of GCS-100, either alone or in combination with dexamethasone, to inhibit tumor growth, overcome drug resistance, and improve outcome for patients with this universally fatal hematologic malignancy.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Boronic Acids / administration & dosage
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dexamethasone / administration & dosage
  • Dexamethasone / pharmacology
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Galectin 3 / antagonists & inhibitors
  • Galectin 3 / biosynthesis
  • Galectin 3 / genetics
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Lymphocytes / cytology
  • Lymphocytes / drug effects
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • NF-KappaB Inhibitor alpha
  • Polysaccharides / administration & dosage
  • Polysaccharides / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Pyrazines / administration & dosage
  • Pyrazines / pharmacology
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / pharmacology


  • Antineoplastic Agents
  • Boronic Acids
  • GCS-100
  • Galectin 3
  • I-kappa B Proteins
  • NFKBIA protein, human
  • Polysaccharides
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazines
  • Vascular Endothelial Growth Factor A
  • NF-KappaB Inhibitor alpha
  • Bortezomib
  • Dexamethasone
  • Doxorubicin