Michael adducts of ascorbic acid as inhibitors of protein phosphatase 2A and inducers of apoptosis

Comparison of the rapid pro-apoptotic effect of trans-ß-nitrostyrenes with delayed apoptosis induced by the standard agent 5-fluorouracil in colon cancer cells

“…As expected from previous results in rat pituitary GH 3 tumour cells [46] and in multidrug resistant HIT hamster B-cells [45] TBNS behaved as a potent inducer of apoptosis in LoVo colon cancer cells as well. We could confirm our conclusions from the MTT viability tests with DNA fragmentation data as well as with biochemical caspase-3 assays where trans-ß-nitrostyrene displayed much faster apoptotic kinetics when compared to 5-fluorouracil.…”

“…It has been reported that trans-ß-nitrostyrene (TBNS) is a potent inhibitor of protein phosphatases PTB1 [44] and PP2A [45] and displays an associated pro-apoptotic effect even in some multidrug resistant tumour cells [45,46].…”

Michael Adducts of Palmitoylascorbic Acid: Effects on the Oxidative Burst of Neutrophils and the Production of Tumor Necrosis Factor-Alpha in Monocytes

“…Apoptosis in mammalian cells can be induced by okadaic acid and related substances [29,30]. In a previous study, it was shown that Michael adducts of ascorbic acids act as inducers of apoptosis of HIT cells, a hamster insulin-secreting cell line that responded with apoptosis to treatment with the phosphatase inhibitors okadaic acid and cantharidic acid [4]. The activation of the apoptosis-specific caspase 3 and the subsequent caspase-activated endonuclease that is responsible for DNA fragmentation were used as characteristic markers of apoptosis.…”

“…For example, compound 2 significantly enhanced caspase 3 activity after 24 h. This was interpreted as a result of the inhibition of PP1 and PP2A. Michael adducts of ascorbic acids might offer the potential for use as cytostatic drugs in multidrug-resistant tumors [4]. With respect to this approach, the failure to enhance the oxidative burst of PMNs might be desirable, since the use of antitumor agents such as doxorubicin [31] or methotrexate [32] is limited due to the formation of reactive oxygen species.…”

“…1) are easily available by a stereospecific Michael addition of palmitoylascorbic acid with acrolein as ·,ß-unsaturated carbonyl compound. Whereas IC 50 values in the lower micromolar range were determined towards PP1 in vitro, an inhibition of PP2A at higher concentrations was detected in a cell culture extract [4]. We have investigated the effects of Michael adducts 1-4 on the phosphorylation-dependent response of stimulated cells.…”