Abstract |
The antiapoptotic protein bcl-x(L) 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-x(L). 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 B9BM-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-x(L), 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-x(L)-expressing tumors.
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Authors | Jonathan B Pollett, Yuan Xiao Zhu, Sonal Gandhi, Meena Bali, Esther Masih-Khan, Zhihua Li, Xiao Yan Wen, A Keith Stewart |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 8
Issue 2
Pg. 230-7
(Aug 2003)
ISSN: 1525-0016 [Print] United States |
PMID | 12907145
(Publication Type: Journal Article)
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Chemical References |
- BCL2L1 protein, human
- Bcl2l1 protein, mouse
- Proto-Oncogene Proteins c-bcl-2
- Receptors, Fibroblast Growth Factor
- bcl-X Protein
- Mifepristone
- FGFR3 protein, human
- Fgfr3 protein, mouse
- Protein-Tyrosine Kinases
- Receptor, Fibroblast Growth Factor, Type 3
- CASP3 protein, human
- Casp3 protein, mouse
- Caspase 3
- Caspases
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Topics |
- Animals
- Apoptosis
(drug effects)
- Caspase 3
- Caspases
(genetics, metabolism, toxicity)
- Cell Line, Tumor
- Enzyme Induction
(drug effects)
- Genetic Therapy
- Genetic Vectors
(genetics)
- Humans
- Mice
- Mifepristone
(pharmacology)
- Multiple Myeloma
(genetics, metabolism, pathology, therapy)
- NIH 3T3 Cells
- Neoplasms, Experimental
- Protein-Tyrosine Kinases
- Proto-Oncogene Proteins c-bcl-2
(genetics, metabolism)
- Receptor, Fibroblast Growth Factor, Type 3
- Receptors, Fibroblast Growth Factor
(genetics, metabolism)
- Retroviridae
(genetics)
- Survival Rate
- Time Factors
- bcl-X Protein
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