Aldehyde dehydrogenases (ALDHs) are a superfamily of several
isoenzymes widely expressed in bacteria, yeast, plant and animals. Three major classes of ALDHs have been traditionally identified, classes 1, 2 and 3. Both exogenous and endogenous
aldehydes, including
aldehydes derived from lipid peroxidation, are oxidized by the ALDH superfamily. Several changes in ALDH
isoenzyme expression take place in
hepatoma cells, in particular cytosolic class 3 ALDH (
ALDH3), not expressed in normal hepatocytes, appears and increases with the degree of deviation. It has been demonstrated that cytosolic
ALDH3 is important in determining the resistance of
tumor cells to
antitumor drugs, such as
cyclophosphamide. Moreover,
hepatoma-associated
ALDH3 seems to be important in metabolizing
aldehydes derived from lipid peroxidation, and in particular the
cytostatic aldehyde 4-hydroxynonenal (4-HNE). We demonstrated previously that restoring endogenous lipid peroxidation in
hepatoma cells by enriching them with
arachidonic acid causes a decrease of
mRNA,
protein and
enzyme activity of
ALDH3 and that this decrease reduces cell growth and/or causes cell death, depending on basal class 3 ALDH activity. To confirm the correlation between inhibition of class 3 ALDH and reduction of cell proliferation, we exposed
hepatoma cells to
antisense oligonucleotides (ODNs) against
ALDH3. In JM2
hepatoma cell line, with high
ALDH3 activity, the exposure to antisense ODNs significantly decreases
mRNA and
enzyme activity (90%). At the same time, cell growth was reduced by about 70%. The results confirm that in
hepatoma cells
ALDH3 expression is closely related with cell growth, and that its inhibition is important in reducing the proliferation of
hepatoma cells overexpressing
ALDH3.