Investigations on gossypol: past and present developments

Abstract

Gossypol has received significant attention as a result of its potential therapeutic application as a male antifertility agent. Furthermore, recent research examining the biological activity of gossypol has revealed a number of other promising lines of enquiry. These have focused on the antitumour, antiviral and antioxidant actions of the compound in various disease states. This article provides an overview of the studies on the biological activity of gossypol, with particular attention paid to the mechanisms of its activity and its prospect as a medicinal product.

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

“…To test this possibility, we focused on gossypol, a bioavailable compound with BH3 functions, which had a safe profile in clinical trials. 23 Natural gossypol (a mixture of (À) and ( þ ) enantiomers) binds Mcl-1, Bcl-2 and Bcl-x L with IC 50 values of 1.74, 0.28 and 3.03 mM, respectively. 20 However, a number of reports have shown that of the two enantiomers, (À)-gossypol is significantly the most potent anticancer agent in vitro and in vivo.…”

“…20 However, a number of reports have shown that of the two enantiomers, (À)-gossypol is significantly the most potent anticancer agent in vitro and in vivo. 23 To estimate the binding affinities of (À)-gossypol for individual Bcl-2 family members, competition fluorescence polarization assays were performed with a fluorescently tagged Bid BH3 peptide. 24 K i values were determined instead of binding concentrations, as they more directly measure the inhibitory capacity of (À)-gossypol.…”

“…However, dysregulation of mitochondrial and redox-dependent functions by gossypol can affect, directly or indirectly, other cellular processes 23 that may act in a BAX/BAK independent manner. 28,29 Therefore, a genetic approach utilizing RNA interference was developed to validate the BH3-dependent function of (À)-gossypol, and to establish the hierarchical requirement of various Bcl-2 family members for viability upon bortezomib treatment.…”

“…Second generation BH3 mimetics based on gossypol are being generated with the objective of improving binding to Mcl-1. 23 These new reagents may ultimately provide a longterm response in combination with bortezomib.…”

“…Among these, the lowest IC 50 values for Mcl-1 have been reported for EGCG and gossypol (0.92 and 1.75 mM, respectively). Gossypol is interesting because, to our knowledge, it is the only bioavailable compound able to bind Mcl-1 23 that is in being tested in phase II clinical trials. 24 In the context of melanoma, gossypol has long been known to kill melanoma cells more efficaciously than normal melanocytes.…”