|
|
Blood, 15 March 2008, Vol. 111, No. 6, pp. 3211-3219.
Prepublished online as a Blood First Edition Paper on January 17, 2008; DOI 10.1182/blood-2007-09-113647.
 Previous Article | Next Article 
Submitted September 18, 2007
Accepted December 22, 2007
Bcl-2 antagonist ApoGossypol (NSC736630) displays single-agent activity in Bcl-2 transgenic mice and has superior efficacy with less toxicity compared to Gossypol (NSC19048)
Shinichi Kitada, Christina L Kress, Maryla Krajewska, Lee Jia, Maurizio Pellecchia, and John C. Reed*
Department of Oncology, Burnham Institute for Medical Research, Cancer Research Center, La Jolla, CA, United States
Department of Oncology, Developmental Therapeutics Program, CDTD/NCI/NIH, Rockville, MD, United States
CLL Research Consortium, San Diego, CA, United States
* Corresponding author; email: reedoffice{at}burnham.org.
Altered expression of Bcl-2-family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product Gossypol and its semi-synthetic derivative ApoGossypol, compounds that bind and inhibit anti-apoptotic Bcl-2 family proteins. Comparisons of growth inhibitory and cytotoxic activity of Gossypol and ApoGossypol using the NCI panel of 60 tumor cell lines, as well as cultured lymphoma cell lines and primary leukemia cells suggested that Gossypol and ApoGossypol have overlapping but non-identical cytotoxic mechanisms. Daily oral dosing studies showed that mice tolerate doses of ApoGossypol 2-4-times higher than Gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of Gossypol, with ApoGossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is over-expressed in B-cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2-expressing B-cells from transgenic mice were more sensitive to cytotoxicity induced by ApoGossypol than Gossypol, with LD50 values of 3-5 µM and 7.5-10 µM, respectively. In vivo, using the maximum tolerated dose of Gossypol (60 µmoles/kg) for sequential daily dosing (daily x 5 days x 3 weeks), ApoGossypol displayed superior activity to Gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2 transgenic mice. At higher doses (120 µmole/kg), at which ApoGossypol but not Gossypol is tolerated, ApoGossypol showed even greater in vivo activity, reducing spleen weight by 40±14% (p<0.001) and splenic B-cell counts by 66±4% (p<0.0001). Taken together, these studies indicate that ApoGossypol is superior to parent compound Gossypol with respect to toxicology and efficacy, suggesting that further development of this compound for cancer therapy is warranted.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
N. Sasi, M. Hwang, J. Jaboin, I. Csiki, and B. Lu
Regulated cell death pathways: New twists in modulation of BCL2 family function
Mol. Cancer Ther.,
June 1, 2009;
8(6):
1421 - 1429.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. V. Rozanov, A. Y. Savinov, V. S. Golubkov, O. L. Rozanova, T. I. Postnova, E. A. Sergienko, S. Vasile, A. E. Aleshin, M. F. Rega, M. Pellecchia, et al.
Engineering a leucine zipper-TRAIL homotrimer with improved cytotoxicity in tumor cells
Mol. Cancer Ther.,
June 1, 2009;
8(6):
1515 - 1525.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Wei, S. Kitada, M. F. Rega, A. Emdadi, H. Yuan, J. Cellitti, J. L. Stebbins, D. Zhai, J. Sun, L. Yang, et al.
Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins
Mol. Cancer Ther.,
April 1, 2009;
8(4):
904 - 913.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. W. Friedberg
Bak to death with chemotherapy
Blood,
June 1, 2008;
111(11):
5263 - 5264.
[Full Text]
[PDF]
|
|
|
|
|
