Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells

Gynecol Oncol. 2003 Apr;89(1):37-47. doi: 10.1016/s0090-8258(03)00006-4.


Objective: We determined the cytotoxic effects BMS 247550 (Epo B), a derivative of epothilone B, on cisplatinum- or paclitaxel-sensitive or -resistant human ovarian cancer cells. Additionally, we determined the effect of Epo B on Apo-2L/TRAIL-induced apoptosis of ovarian cancer cells.

Methods: Epo B-induced cytotoxic and cell cycle effects were evaluated by the MTT assay and flow cytometry, respectively. Epo B-induced apoptosis was assessed by immunoblot analyses of the processing and proteolytic activity of caspases, flow cytometric measurement of annexin V staining, and the TUNEL assay. The effects of Epo B and/or Apo-2L/TRAIL on the protein expressions of the death receptors DR4 and DR5 as well as of XIAP and survivin were determined by immunoblot analyses.

Results: In the cell cycle-synchronized ovarian cancer cells, Epo B induced tubulin polymerization and mitotic arrest, followed by apoptosis. This was associated with the cytosolic accumulation of cytochrome (cyt) c and Smac/DIABLO as well as PARP cleavage activity of caspase-3. Epo B was able to exert cytotoxic effects against cisplatinum- and paclitaxel-resistant ovarian cancer cells. Epo B increased the expressions of DR4 and DR5, as well as augmented Apo-2L/TRAIL-induced processing of caspase-8 and Bid. This was associated with more caspase-3 activity, a decline in the intracellular levels of XIAP, cIAP, and survivin, and apoptosis of ovarian cancer cells.

Conclusions: These data support the in vivo testing of Epo B against cisplatinum- and paclitaxel-resistant ovarian cancers, and suggest that a pretreatment with Epo B may sensitize human ovarian cancers to the cytotoxic effects of Apo-2L/TRAIL.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Caspase 3
  • Caspases / metabolism
  • Cisplatin / pharmacology
  • Cytochrome c Group / metabolism
  • Down-Regulation / drug effects
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Epothilones / administration & dosage
  • Epothilones / pharmacology*
  • Female
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Membrane Glycoproteins / administration & dosage
  • Membrane Glycoproteins / pharmacology*
  • Microtubule-Associated Proteins / biosynthesis
  • Mitosis / drug effects
  • Neoplasm Proteins
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Paclitaxel / pharmacology
  • Protein Biosynthesis
  • Proteins*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Survivin
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / pharmacology*
  • X-Linked Inhibitor of Apoptosis Protein


  • Apoptosis Regulatory Proteins
  • BIRC5 protein, human
  • Cytochrome c Group
  • Epothilones
  • Inhibitor of Apoptosis Proteins
  • Membrane Glycoproteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • Survivin
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • ixabepilone
  • Paclitaxel
  • Cisplatin