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 semisynthetic derivative apo-
gossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family
proteins. Daily oral dosing studies showed that mice tolerate doses of
apogossypol 2- to 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 overexpressed 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 to 5 microM and 7.5 to 10 microM, respectively. In vivo, using the maximum tolerated dose of
gossypol for sequential daily dosing,
apogossypol displayed superior activity to
gossypol in terms of reducing
splenomegaly and reducing B-cell counts in spleens of Bcl-2-transgenic mice. 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.