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Bcl-2 antisense oligonucleotide overcomes resistance to E1A gene therapy in a low HER2-expressing ovarian cancer xenograft model.
- Source :
-
Cancer research [Cancer Res] 2005 Sep 15; Vol. 65 (18), pp. 8406-13. - Publication Year :
- 2005
-
Abstract
- We are currently conducting clinical trials of E1A gene therapy for patients with ovarian cancer. The adenovirus type 5 E1A gene suppresses growth of ovarian cancer cells that overexpress HER-2/neu (HER2) and growth of some--but not all--that express low HER2. In HER2-overexpressing cells, suppression by E1A is predominantly by down-regulation of HER2, but the mechanism in low HER2-expressing cells is not fully understood. The adenoviral E1B protein has sequential and functional homology to Bcl-2 and prolongs the viability of adenovirus host cells by inhibiting E1A-induced apoptosis. Bcl-2 is overexpressed in ovarian cancer and participates in chemoresistance; we hypothesized that Bcl-2 inhibits E1A-induced apoptosis leading to resistance to E1A gene therapy. E1A suppressed colony formation of ovarian cancer cells that express low levels of Bcl-2 and HER2 (OVCAR-3 and OVCA 433), but enhanced colony formation in low HER2-, high Bcl-2-expressing ovarian cancer cells (2774 and HEY). Treating 2774 or HEY cells with antisense oligonucleotide Bcl-2 (Bcl-2-ASO) did not reduce cell viability. E1A combined with Bcl-2-ASO led to significant decreases in cell viability resulting from increased apoptosis relative to cells treated with E1A alone (P < 0.05). The increase in apoptosis was partly due to cytochrome c release and subsequently caspase-9 activation by Bcl-2-ASO. Finally, in an ovarian cancer xenograft model, treatment with Bcl-2-ASO did not prolong survival, but E1A plus Bcl-2-ASO did (P < 0.001). In conclusion, ovarian tumors overexpressing Bcl-2 may not respond well to E1A gene therapy, but treatment with a combination of E1A and Bcl-2-ASO may overcome this resistance.
- Subjects :
- Animals
Apoptosis genetics
Caspase 9
Caspases metabolism
Cell Line, Tumor
Cytochromes c metabolism
Enzyme Activation
Female
Humans
Mice
Mice, Nude
Oligonucleotides, Antisense
Ovarian Neoplasms genetics
Ovarian Neoplasms metabolism
Receptor, ErbB-2 genetics
Thionucleotides biosynthesis
Transfection
Xenograft Model Antitumor Assays
Adenovirus E1B Proteins genetics
Genetic Therapy methods
Ovarian Neoplasms therapy
Receptor, ErbB-2 biosynthesis
Thionucleotides genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 65
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 16166319
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-05-1754