Background:
The α-oxo-aldehydes glyoxal and methylglyoxal are byproducts of fatty acid oxidation
and glycolysis. Cancer cells produce significantly more of these aldehydes than other
cells due to their high glycolytic activity. These substances are highly reactive
and modify proteins. As a result stable, accumulating products, the so called advanced
glycation end products (AGEs)are formed. In this study we analysed the responses of
the estrogen receptor positive mamma carcinoma cell line MCF-7 to glyoxal and methylglyoxal.
Methods:
Cell vitality was determined by the resazurin assay. Activation of MAP-kinases and
NF-κB was determined by Western blotting. Oxidative stress was measured by loading
the cells with the oxidation-sensitive fluorochrome dihydrofluorescein-diacetate.
Results:
Dialdehydes resulted in cell death in low millimolar concentrations. Cells exposed
to the aldehydes responded by a rapid activation of MAP-kinase signalling and production
of reactive oxygen species as well as activation of caspase 3/7 activity, finally
leading to cell death. Interestingly, a tamoxifen resistant derivative of MCF-7 showed
an additional activation of the NF-κB transcription factor by methylglyoxal only and
was altogether more sensitive to the aldehydes. Addition of the antioxidant N-acetyl
cystein protected the cells, demonstrating that oxidative stress was a major cause
of cell death.
Conclusions:
These data demonstrate that exogenous aldehyde stress is cytotoxic to mamma carcinoma
cells by causing severe oxidative stress. Inhibition of aldehyde defence enzymes such
as glyoxalases might therefore be a promising therapeutic option against breast cancer.
