1. Michael adducts of ascorbic acid as inhibitors of protein phosphatase 2A and inducers of apoptosis.
- Author
-
Fathi AR, Krautheim A, Kaap S, Eger K, and Steinfelder HJ
- Subjects
- Animals, Apoptosis physiology, Ascorbic Acid chemical synthesis, Ascorbic Acid chemistry, Caspase 3, Caspases metabolism, Cell Line, Cricetinae, DNA Fragmentation drug effects, Drug Design, Enzyme Activation, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Indicators and Reagents, Kinetics, Molecular Structure, Protein Phosphatase 1, Protein Phosphatase 2, Structure-Activity Relationship, Apoptosis drug effects, Ascorbic Acid analogs & derivatives, Ascorbic Acid pharmacology, Enzyme Inhibitors chemical synthesis, Phosphoprotein Phosphatases antagonists & inhibitors
- Abstract
Michael adducts of ascorbic acid with alpha,beta-unsaturated carbonyl compounds have been shown to be potent inhibitors of protein phosphatase 1 (PP1) without affecting cell viability at the respective concentrations. Here we were able to show that higher concentrations can partially inhibit PP2A activity and concomitantly induce apoptotic cell death. A nitrostyrene adduct of ascorbic acid proved to be a more potent and effective inhibitor of PP2A as well as a stronger inducer of apoptosis. These adducts only slightly lost their cytotoxic potential in multidrug resistant cells that were 10-fold less sensitive to apoptosis induction by okadaic acid and vinblastine.
- Published
- 2000
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