Quantitative determination of apogossypol, a pro-apoptotic analog of gossypol, in mouse plasma using LC/MS/MS

Coward, Lori; Gorman, Gregory S.; Noker, Patricia E.; Kerstner-Wood, Corenna; Pellecchia, M.; Reed, John C.; Jia, Lee

doi:10.1016/j.jpba.2006.05.020

Cited by 22 publications

(25 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Apogossypol Is Less Toxic Than Gossypolmentioning

confidence: 99%

“…Ascorbic acid was used as a control, because apogossypol is formulated at 1:1 molar ratio with this weak acid, which renders the compound stable upon storage. 22 Compounds or vehicle control were dosed 15 times over 3 weeks; compounds were given daily for 5 consecutive days (Monday-Friday), resting on weekends.In terms of gross appearance, gossypol was toxic in 23 of 23 mice, as evidenced by lethargic behavior as well as scruffy and rough hair. No such toxicity was seen in 38 of 40 mice treated with apogossypol or in 20 of 20 mice treated with vehicle control.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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)

Kitada

Kress

Krajewska

et al. 2008

Blood

View full text Add to dashboard Cite

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 ...

show abstract

Section: Apogossypol Is Less Toxic Than Gossypolmentioning

confidence: 99%

mentioning

confidence: 99%

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)

Kitada

Kress

Krajewska

et al. 2008

Blood

View full text Add to dashboard Cite

show abstract

“…Whilst binding analyses failed to show preferential activity for either enantiomer both had better affinity for Bcl-x L and Mcl-1 than the racemate (albeit marginally) [118]. Apogossypol has an improved pharmacokinetic profile compared to Gossypol with increased blood concentration due to lower clearance rate [119]. In animal models, apogossypol proved to be more efficacious and markedly less toxic than gossypol [120].…”

Section: Apogossypol and Derivativesmentioning

confidence: 95%

Bcl-2 Family Proteins as Therapeutic Targets

Czabotar¹,

Lessène

2010

CPD

View full text Add to dashboard Cite

The mitochondrion provides the stage for the interplay of molecular interactions that regulate apoptosis via the intrinsic pathway. The release of apoptogenic factors from this compartment constitutes a critical juncture in this apoptotic pathway. Regulation of the integrity of the outer mitochondrial membrane (OMM) is the task of the Bcl-2 family of proteins. A network of interactions between the various subgroups of the family decides the apoptotic fate of a cell and, as such, an imbalance within this network can lead to a variety of disease states. In particular, over-expression of pro-survival Bcl-2 family proteins is a hallmark of many cancers. Here we discuss recent advances in targeting the Bcl-2 family with both peptides and small molecules.

show abstract

“…Recently we also evaluated single-dose pharmacokinetic characteristics of Apogossypol in mice, revealing superior blood concentrations over time (AUC) compared to Gossypol, due to slower clearance of the compound [14].…”

Section: Clinical and Translational Leadsmentioning

confidence: 99%

Targeting Apoptosis via Chemical Design

Pellecchia¹,

Wei²,

Kitada³

et al. 2008

AACR Education book

Self Cite

View full text Add to dashboard Cite

Anti-apoptotic Bcl-2 family proteins such as Bcl-2 and Bcl-x L have recently been validated as targets for the discovery of novel anti-cancer agents. Gossypol, a natural product extracted from cottonseeds, is an eff ective pro-apoptotic compound targeting anti-apoptotic Bcl-2 family proteins and its (−) enantiomer (AT101), is currently under clinical investigation. Th e interaction of this natural product with Bcl-x L was characterized biophysically and in in vitro displacement assays. Aided by a model of the docked structure of Gossypol into its target, Bcl-x L , we were able to predict modifi cations of the natural product on a rational basis. We show that such modifi cations lead to the analog Apogossypol, which lacks two likely reactive aldehydic groups and displays a pro-apoptotic activity comparable to Gossypol. Recently, we compared the effi cacy and toxicity in mice of (−) Gossypol (AT101) and (+/−) Apogossypol (CNDO103). Our preclinical in vivo data supports the hypothesis that (+/−) Apogossypol has superior effi cacy and markedly reduced toxicity compared to (−) Gossypol. Single-dose pharmacokinetic characteristics of (+/−) Apogossypol in mice, also reveal superior blood concentrations over time compared to (−) Gossypol, due to slower clearance of the compound. Th ese comparative pharmacological and toxicity evaluations strongly suggest that Apogossypol represents a valid lead candidate for the development of novel anti-cancer therapies.

show abstract

Quantitative determination of apogossypol, a pro-apoptotic analog of gossypol, in mouse plasma using LC/MS/MS

Cited by 22 publications

References 10 publications

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)

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)

Bcl-2 Family Proteins as Therapeutic Targets

Targeting Apoptosis via Chemical Design

Contact Info

Product

Resources

About