Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)

Abstract

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 apogossypol, 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 M and 7.5 to 10 M, 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. IntroductionOverexpression of Bcl-2 and other antiapoptotic members of the Bcl-2 family occurs in many human cancers and leukemias. [1][2][3] Bcl-2 and related antiapoptotic proteins suppress tumor cell death induced by chemotherapy, radiation, hormonal therapies (including glucocorticoids), and other therapeutics used in the treatment of malignancy. [4][5][6] Thus, agents that inhibit antiapoptotic Bcl-2 family proteins are desired as potential new therapeutics for restoring apoptosis sensitivity and improving clinical outcomes for patients with cancer or leukemia.Bcl-2 has been validated as a target for improving treatment of B-cell malignancies using Bcl-2 antisense oligodeoxynucleotides to reduce Bcl-2 protein expression. 7 The Bcl-2 antisense drug candidate, oblimersen sodium (Genasense; Genta, Berkeley Heights, NJ), for example, improved complete response rates and prolonged response duration in a randomized phase 3 clinical trial involving patients with relapsed or refractory chronic lymphocytic leukemia (CLL). 8 Moreover, the BCL-2 gene becomes activated by chromosomal translocations or gene amplification in the majority of non-Hodgkin B-cell lymphomas (B-NHLs), while its overexpression is found in most chronic lymphocytic leukemias (CLLs) in association with chromosomal deletions of microRNA (miR)-encoding genes that normally suppress Bcl-2 expression. [9][10][11] In this study, we compared the toxicity and efficacy in mice of gossypol (NSC19048) and apogossypol (NSC736630), a semisynthetic analog of natural product gossypol, in which 2 reactive aldehydes were eliminated from the compound. 12 Gossypol and apogossypol ...

Different forms of cell death induced by putative BCL2 inhibitors

“…17 Removal of the two reactive aldehyde groups in gossypol resulted in the synthesis of apogossypol, with similar binding kinetics to BCL2 and BCL-X L but with reduced toxicity in vivo. 17,21 Initially described as a selective protein kinase C inhibitor, 22 chelerythrine, a naturally occurring benzophenanthridine alkaloid, was subsequently identified by high throughput screening as an inhibitor of BCL-X L . 19 EM20-25, which binds to the BH3 domain of BCL2, is a derivative of HA14-1, but lacks its effects on mitochondrial respiration.…”

Influence of gossypol acetic acid on the growth of human adenoid cystic carcinoma ACC-M cells and the expression of DNA methyltransferase 1

“…Additionally, long-term oral dose of gossypol could not induce myelosuppression (Oliver et al, 2005). A study reported that gossypol could induce an increase in aspartate aminotransferase and alanine aminotransferase, but had no significant influence on the kidneys, heart, and blood cells (Kitada et al, 2008).…”

A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria

“…NMR and fluorescence polarization competitive binding experiments demonstrated that gossypol can bind to the BH3 domain of the Bcl-2 family antiapoptotic proteins in the tumor cells thus initiating caspasedependent apoptosis events (3). However, the clinical use of gossypol is limited by its toxicity problem most likely due to two reactive aldehyde groups and by its high hydrophobicity (4). As a result, many derivatives of gossypol have been generated including AT-101 and ApoG2 that have entered clinical trials (4).…”