Carcinogenesis. 2004 Jan 30 [Epub ahead of print]
Wenzel U, Nickel A, Kuntz S, Daniel H.
Molecular Nutrition Unit, Department of Food and Nutrition, Technical University of Munich, Hochfeldweg 2, D-85350 Freising, FRG.
Although a high alimentary intake of antioxidant vitamins such as ascorbic acid may play an important role in cancer prevention, a high level of antioxidants may have quite different effects at different stages of the transformation process. In cancer development, the resistance of cells to apoptosis is one of the most crucial steps. We have tested the effects of acorbic acid on apoptosis in HT-29 human colon carcinoma cells when induced by two potent apoptosis inducers, the classical anti-tumor drug camptothecin or the flavonoid flavone.
Apoptosis was assessed based on caspase-3-like activity, plasma membrane disintegration and finally nuclear fragmentation and chromatin condensation. Ascorbic acid dose-dependently inhibited the apoptotic response of cells to camptothecin and flavone. RT-PCR analysis and Western-blot analysis revealed that ascorbic acid specifically blocked the decrease of bcl-XL by camptothecin or flavone. An increased generation of mitochondrial O2(-). precedes the down-regulation of bcl-XL by camptothecin and flavone and ascorbic acid at a concentration of 1 mM prevented the generation of this reactive oxygen species.
In conclusion, ascorbic acid functions as a potent antioxidant in mitochondria of human colon cancer cells and thereby blocks drug-mediated apoptosis induction allowing cancer cells to become insensitive to chemotherapeutics.
PMID: 14754875 [PubMed – as supplied by publisher]