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

Abstract

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.

• Authors: David Griffin, Sylvie Wittmann, Fei Guo, Ramadevi Nimmanapalli, Purva Bali, Hong Gang Wang, Kapil Bhalla
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 89 Issue 1 Pg. 37-47 (Apr 2003) ISSN: 0090-8258 [Print] United States
• PMID: 12694652 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, 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, pharmacology)
• Female
• Humans
• Inhibitor of Apoptosis Proteins
• Membrane Glycoproteins (administration & dosage, pharmacology)
• Microtubule-Associated Proteins (biosynthesis)
• Mitosis (drug effects)
• Neoplasm Proteins
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Paclitaxel (pharmacology)
• Protein Biosynthesis
• Proteins
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Recombinant Proteins (administration & dosage, pharmacology)
• Survivin
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (administration & dosage, pharmacology)
• X-Linked Inhibitor of Apoptosis Protein