Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease

Gynecol Oncol. 2005 Feb;96(2):287-95. doi: 10.1016/j.ygyno.2004.10.026.

Abstract

Objective: The long-term survival of patients with epithelial ovarian cancer is limited by the emergence of tumor cells that are resistant to chemotherapy. We hypothesized that expression of Bcl-x(L), a homologue of Bcl-2 that confers protection from chemotherapy-induced apoptosis, may be predictive of patients' clinical response to treatment, and that treatment with chemotherapy may result in the selection of tumor cells that overexpress this protein.

Methods: We determined the expression of Bcl-x(L) in epithelial ovarian cancers from 28 patients at the time of initial staging laparotomy and in recurrent tumors in the same patients following treatment with platinum-based chemotherapy. The data were analyzed to determine whether Bcl-x(L) expression was predictive of clinical outcome. A2780 ovarian cancer cells were stably transfected with Bcl-x(L) or control plasmid. Chemotherapy-induced apoptosis in these cell lines was determined in vitro and in a xenograft model.

Results: Bcl-x(L) expression in primary tumors was associated with a significantly shorter disease-free interval as compared to patients whose tumors did not express Bcl-x(L) (1.6 months as compared to 7.7 months). We found that Bcl-x(L) expression conferred resistance to chemotherapy-induced apoptosis resulting from treatment with cisplatin, paclitaxel, topotecan, and gemcitabine in vitro. In a xenograft model, Bcl-x(L) expressing tumors continued to grow following treatment with cisplatin, paclitaxel, topotecan, and gemcitabine, in contrast to control tumors, which disappeared.

Conclusion: These results portray an important role for Bcl-x(L) as a key factor associated with chemotherapy failure in the treatment of ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Mice
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Paclitaxel / administration & dosage
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Topotecan / administration & dosage
  • Xenograft Model Antitumor Assays
  • bcl-X Protein

Substances

  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Deoxycytidine
  • Topotecan
  • gemcitabine
  • Paclitaxel
  • Cisplatin