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Bcl-2 antisense oligonucleotide overcomes resistance to E1A gene therapy in a low HER2-expressing ovarian cancer

Chandra Bartholomeusz1, Hiroaki Itamochi, Linda X H Yuan

  • 1Breast Cancer Translational Research Laboratory, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

Cancer Research
|September 17, 2005
PubMed

Insights

E1A gene therapy shows promise for ovarian cancer, but resistance occurs when Bcl-2 is overexpressed. Combining E1A with Bcl-2 antisense oligonucleotide therapy overcomes this resistance by increasing apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Ovarian cancer exhibits variable response to E1A gene therapy, influenced by HER2 and Bcl-2 expression levels.
  • Adenoviral E1A gene suppresses ovarian cancer cell growth, primarily through HER2 downregulation in HER2-overexpressing cells.
  • Adenoviral E1B protein inhibits apoptosis, and Bcl-2 overexpression in ovarian cancer contributes to chemoresistance, potentially hindering E1A gene therapy efficacy.

Purpose of the Study:

  • To investigate the role of Bcl-2 in mediating resistance to E1A gene therapy in ovarian cancer.
  • To evaluate the efficacy of combining E1A gene therapy with Bcl-2 antisense oligonucleotide (Bcl-2-ASO) in overcoming resistance.

Main Methods:

  • Assessed E1A gene therapy's effect on ovarian cancer cell lines with varying HER2 and Bcl-2 expression.
  • Treated cells with Bcl-2-ASO alone and in combination with E1A.
  • Measured cell viability, apoptosis, cytochrome c release, and caspase-9 activation.
  • Evaluated therapeutic efficacy in an ovarian cancer xenograft model.

Main Results:

  • E1A suppressed colony formation in low Bcl-2/HER2 ovarian cancer cells but enhanced it in low HER2/high Bcl-2 cells.
  • Bcl-2-ASO alone did not reduce cell viability, but its combination with E1A significantly decreased viability and increased apoptosis.
  • The combination therapy induced apoptosis via cytochrome c release and caspase-9 activation.
  • In vivo, E1A plus Bcl-2-ASO significantly improved survival in ovarian cancer xenografts.

Conclusions:

  • Ovarian tumors overexpressing Bcl-2 may exhibit resistance to E1A gene therapy.
  • Combining E1A gene therapy with Bcl-2-ASO can overcome Bcl-2-mediated resistance by enhancing apoptosis.
  • This combination therapy presents a potential strategy to improve treatment outcomes for resistant ovarian cancers.

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