NOV-002, a Glutathione Disulfide Mimetic, as a Modulator of Cellular Redox Balance

Abstract

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 dosedependent 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.

Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

“…A unique antitumor agent NOV-002, a stabilized formulation of GSSG and cisplatin at a ratio of 1000:1, (developed by Novelos and now Cellectar Biosciences, Inc.), has been reported to alter the GSH:GSSG ratio by acting as a competitive substrate for gamma-glutamyl-transpeptidase (GGT) (105). GGT catalyzes the transfer of the gammaglutamyl moiety of GSH to an acceptor protein to give Sglutathionylation proteins.…”

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…clinical and clinical studies demonstrates that pharmacological administration of the oxidized form of glutathione, glutathione disulfide (GSSG), exerts significant anticancer activity based on modulation of cellular redox homeostasis, as reviewed recently (346,347). A complex of glutathione disulfide with cis-platinum at an approximate ratio of 1000:1 (NOV-002) has shown clinical efficacy in combination with chemotherapy in the treatment of NSCLC, a significant redox chemotherapeutic intervention currently being evaluated in an ongoing pivotal Phase III trial that builds on earlier studies that indicated therapeutic benefit of NOV-002 codaministration in patients with advanced NSCLC receiving cisplatin and paclitaxel standard chemotherapy (ClinicalTrials.gov Identifier: NCT00347412).…”

“…A complex of glutathione disulfide with cis-platinum at an approximate ratio of 1000:1 (NOV-002) has shown clinical efficacy in combination with chemotherapy in the treatment of NSCLC, a significant redox chemotherapeutic intervention currently being evaluated in an ongoing pivotal Phase III trial that builds on earlier studies that indicated therapeutic benefit of NOV-002 codaministration in patients with advanced NSCLC receiving cisplatin and paclitaxel standard chemotherapy (ClinicalTrials.gov Identifier: NCT00347412). In HL-60 human leukemia, NOV-002 or GSSG administered in the absence of cisplatin induced a significant prooxidant deviation from redox homeostasis based on increased intracellular levels of H 2 O 2 , a decreased GSH:GSSG ratio, and extensive S-glutathionylation of intracellular proteins, including actin associated with a changed cytoskeletal morphology (346). Moreover, GSSG-induced protein S-glutathionylation was accompanied by activating phosphorylation of the MAPK pathway kinases JNK, ERK, and p38, consistent with earlier work on MAPK activation by GSSG administration.…”

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

“…Free sulfhydryls in the nucleus accumbens were measured as previously described (Townsend et al, 2008(Townsend et al, , 2009. Briefly, 100 mg of protein from homogenized brain tissue lysate was passed through BioSpin6 (Bio-Rad, Hercules, CA) micro-column that retains both GSH and GSSG.…”