Scheme XX.

MnP inactivates complexes I and III via their S-glutathionylation when combined with dexamethasone in lymphoma cellular model. MnTE-2-PyP⁵⁺ was tested in lymphoma cellular model where it enhanced cell killing in the presence of dexamethasone via enhancing H₂O₂ production [45,46]. H₂O₂ in turn was employed by MnP to catalyze S-glutathionylation of protein thiols. Such action, depicted in Scheme XI, is in essence either GPx- or thiol oxidase-like activity of MnP. Such oxidative modification has been demonstrated on both cytosolic and mitochondrial levels. In cytosol cysteine units of p50 and most so p65 of NF-kB seem to be modified, while complexes I, III and IV were S-glutathionylated in mitochondria. Also oxidation of p50 by MnP in nucleus has been suggested by Piganelli's group [48]. All proteins except complex IV (though S-glutathionylated) were inactivated by such oxidative modifications. That indicates that MnP under conditions of high oxidative stress, i.e. high H₂O₂ levels, which may be produced by different treatment modalities such as radiation and chemotherapy (dexamethasone or ascorbate or temozolomide, [3,41,42,44,45,47,53], would suppress anti-apoptotic, survival pathways and cellular energetics, killing cancer cell on two metabolic fronts. Adapted from [45,46].