Abstract
The antiapoptotic protein bcl-xL is upregulated in a variety of solid tumors and in primary hematologic malignancies such as multiple myeloma. Activated caspase-3 cleaves proteins essential for cell survival, including bcl-xL. To explore the potential of caspase-3 as a cytotoxic and immunostimulatory molecule in the treatment of malignancy, an RU486-inducible caspase-3 retrovirus was constructed, validated, and used to transduce first 3T3 and subsequently murine myeloma B9BM1 cells (creating the cell line B9BM-C3). After induction, apoptotic cell death of 3T3 and B98M-C3 cells began by 4 h and was complete by 48 h postinduction, while nontransduced cells remained viable. Annexin V staining demonstrated 43, 76, and 98% apoptotic cell death at 12, 18, and 24 h postinduction. Activation of caspase-3 was evident in induced cells and cell death could be inhibited by the addition of a caspase-3-specific inhibitor. Overexpression of the myeloma-associated oncogene FGFR3, which upregulates bcl-xL, delayed but did not prevent caspase-3-mediated killing. B9BM-C3 cells formed tumors after subcutaneous injection in mice. Early treatment with RU486 eradicated tumors; however, rechallenge of treated mice failed to demonstrate evidence of immunoprotection. These results indicate that therapeutic attempts to induce caspase-3 in malignant cells may prove useful in the treatment of bcl-xL-expressing tumors.
Original language | English (US) |
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Pages (from-to) | 230-237 |
Number of pages | 8 |
Journal | Molecular Therapy |
Volume | 8 |
Issue number | 2 |
DOIs | |
State | Published - Aug 1 2003 |
Keywords
- Apoptosis
- Caspase-3
- Myeloma
- RU486
- Retrovirus
- bcl-x
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery