Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells.
Gynecol Oncol
; 89(1): 37-47, 2003 Apr.
Article
en En
| MEDLINE
| ID: mdl-12694652
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
/
Glicoproteínas de Membrana
/
Proteínas
/
Protocolos de Quimioterapia Combinada Antineoplásica
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Factor de Necrosis Tumoral alfa
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Apoptosis
/
Epotilonas
Límite:
Female
/
Humans
Idioma:
En
Revista:
Gynecol Oncol
Año:
2003
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos