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
methional-inducible 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.