We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
RU486-inducible retrovirus-mediated caspase-3 overexpression is cytotoxic to bcl-x<sub>l</sub>-expressing myeloma cells in vitro and in vivo
- Authors
Pollett, Jonathan B.; Zhu, Yuan-Xiao; Gandhi, Sonal; Bali, Meena; Masih-Khan, Esther; Li, Zhihua; Wen, Xiao-Yan; Stewart, A. Keith
- 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 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-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.
- Subjects
RETROVIRUSES; CELL death; TUMORS
- Publication
Molecular Therapy, 2003, Vol 8, Issue 2, p230
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/S1525-0016(03)00146-1