α,β-Acetylenic Amino Thiolester Inhibitors of Aldehyde Dehydrogenases 1&3: Suppressors of Apoptogenic Aldehyde Oxidation and Activators of Apoptosis

G.      Fournet; G.      Martin; G.      Quash

doi:10.2174/0929867311320040004

Abstract

The aim of this minireview is to recapitulate the evidence in the literature supporting a role for the aldehyde dehydrogenases (ALDH1, ALDH2 and ALDH3) in controlling the levels of 3 endogenous apoptogenic aldehydes: methional, malondialdehyde (MDA) and 4-hydroxynonenal (HNE). All 3 aldehydes are formed during the metabolism of cellular constituents. Methional is derived from the oxidative decarboxylation of 4-methylthio-2-oxobutanoate coming from the methionine salvage pathway. MDA arises from the peroxidation of lipids and also from methional subjected to attack by reactive oxygen species (ROS). HNE is formed primarily from lipid peroxidation by ROS attack. One major origin of ROS is the dysfunctional electron transport chain in the mitochondria of cancer cells. As bifunctional electrophilic compounds, HNE forms adducts with cellular nucleophiles e.g. GSH, whilst MDA acts as a potent DNA/protein cross-linking agent in vitro and in vivo. Cancer cells protect themselves from the apoptogenic effect of these aldehydes by the ALDHs that oxidize them to their non-apoptogenic carboxylic acids. Indeed, the over-expression of ALDH3 protects cells from HNE-induced apoptosis. The inhibition of ALDH1 allows methional to reach its apoptogenic threshold in BAF3bcl2 that were resistant to methionalinducible apoptosis. One member of the α,β-acetylenic N-substituted aminothiol ester family is an “active-enzyme-dependent”, competitive, irreversible inhibitor of ALDH1 in vitro, an inhibitor of ALDH1 and ALDH3 in rat and human cancer cells in culture, an irreversible apoptogen on chemoresistant bcl2+++ murine lymphoid and human epithelial cancer cells but a reversible cytostatic compound on human prostate epithelial normal cells in culture.

Keywords: Apoptogenic aldehydes, aldehyde dehydrogenases, ALDH inhibitors, cancer, bcl2, endogenous apoptogenic, aldehydes, methional, malondialdehyde (MDA), oxidative decarboxylation, 4-methylthio-2-oxobutanoate