Michael adducts of ascorbic acid as inhibitors of protein phosphatase 2A and inducers of apoptosis.
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.
Fathi
A R
AR
Institut für Pharmakologie, Universität Göttingen, Germany.
Krautheim
A
A
Kaap
S
S
Eger
K
K
Steinfelder
H J
HJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D053938:DNA Fragmentation / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D015394:Molecular Structure; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D053148:Caspase 3; D020169:Caspases; D001205:Ascorbic Acid