NOV-002 is a novel
glutathione disulfide mimetic that when administered in combination with standard chemotherapeutic regimens has resulted in increased efficacy (survival,
tumor response) and improved tolerance to
chemotherapy (e.g., hematologic recovery) in advanced
non-small cell lung cancer patients. We show that
NOV-002, which is not cytotoxic as a single agent, generated time- and concentration-dependent oxidative signals at the cell surface (reduction in
protein thiols) and intracellularly [altered
oxidized glutathione (
GSSG) and
reduced glutathione levels and ratio; increased
reactive oxygen species] in the premyeloid HL-60 cell line and that this was associated with an increase in S-glutathionylation of cell
proteins, particularly actin. Commensurate with these effects,
NOV-002 activated p38, c-Jun-NH(2)-kinase, and
extracellular signal-regulated kinase and caused a dose-dependent increase in phosphorylation of three
proteins that have previously been linked with hematopoiesis, AKT, JAK2, and STAT5. The effect of
NOV-002 on
enzymes involved in
glutathione metabolism was evaluated. Relative to
oxidized glutathione,
NOV-002 was an equivalent substrate for
glutathione reductase and was an inhibitor of
protein disulfide isomerase, one of the components of the redox-sensitive unfolded protein response pathway. These redox-stimulated cell signaling actions occurred in the context of increased HL-60 cell proliferation
after treatment with
NOV-002. Overall, the pleiotropic pharmacologic effects of
NOV-002 can be attributed to the
GSSG component of the
drug, and modulation of cellular redox balance is a feature central to the mechanism of action of
NOV-002. Such modulation may underlie its clinical actions, including hematologic recovery and immunostimulation in the face of chemosuppression.