Ascorbic acid suppresses drug-induced apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions.
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 ascorbic acid on apoptosis in HT-29 human colon carcinoma cells when induced by two potent apoptosis inducers, the classical antitumor 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-X(L) by camptothecin or flavone. An increased generation of mitochondrial O(2)(-.) precedes the down-regulation of bcl-X(L) 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.
Wenzel
Uwe
U
Molecular Nutrition Unit, Department of Food and Nutrition, Technical University of Munich, Hochfeldweg 2, D-85350 Freising, Germany. uwenzel@wzw.tum.de
Nickel
Alexander
A
Kuntz
Sabine
S
Daniel
Hannelore
H
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D015151:Immunoblotting; D008928:Mitochondria / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism*; D051020:bcl-X Protein
D000975:Antioxidants; C494811:BCL2L1 protein, human; D047309:Flavones; D005419:Flavonoids; D016166:Free Radical Scavengers; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D013481:Superoxides; D017665:Hydroxyl Radical; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D001205:Ascorbic Acid; C043562:flavone; D002166:Camptothecin