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RU486-inducible retrovirus-mediated caspase-3 overexpression is cytotoxic to bcl-xL-expressing myeloma cells in vitro and in vivo.

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.
AuthorsJonathan B Pollett, Yuan Xiao Zhu, Sonal Gandhi, Meena Bali, Esther Masih-Khan, Zhihua Li, Xiao Yan Wen, A Keith Stewart
JournalMolecular 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
PMID12907145 (Publication Type: Journal Article)
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
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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