ApoGossypol May Work Better, Show Less Toxicity than Gossypol

[Guest guest]

[Gossypol has been the subject of clinical trials in CLL. This analog

may work better, show fewer side effects.]

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, L Kress, la Krajewska, Lee Jia,

Maurizio Pellecchia, and C. *

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

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.