nov-002 and Neoplasms

Anticancer drug development using the platform of glutathione (GSH), glutathione S-transferases (GST) and pathways that maintain thiol homeostasis has recently produced a number of lead compounds. GSTpi is a prevalent protein in many solid tumors and is overexpressed in cancers resistant to drugs. It has proved to be a viable target for pro-drug activation with at least one candidate in late-stage clinical development. In addition, GSTpi possesses noncatalytic ligand-binding properties important in the direct regulation of kinase pathways. This has led to the development and testing of agents that bind to GSTpi and interfere with protein-protein interactions, with the phase II clinical testing of one such drug. Attachment of glutathione to acceptor cysteine residues (glutathionylation) is a posttranslational modification that can alter the structure and function of proteins. Two agents in preclinical development (PABA/NO, releasing nitric oxide on GST activation, and NOV-002, a pharmacologically stabilized pharmaceutical form of GSSG) can lead to glutathionylation of a number of cellular proteins. The biological significance of these modifications is linked with the mechanism of action of these drugs. In the short term, glutathione-based systems should continue to provide viable targets and a platform for the development of novel cancer drugs.

Topics: 4-Aminobenzoic Acid; Animals; Antineoplastic Agents; Azo Compounds; Cisplatin; Cytotoxins; Drug Combinations; Glutathione; Glutathione Disulfide; Glutathione Transferase; Humans; Molecular Structure; Neoplasms; Oxidative Stress; para-Aminobenzoates; Prodrugs; Protein Kinases; Signal Transduction

Many cancer drugs impact cancer cell redox regulatory mechanisms and disrupt redox homeostasis. Pharmacodynamic biomarkers that measure therapeutic efficacy or toxicity could improve patient management. Using immunoblot analyses and mass spectrometry, we identified that serpins A1 and A3 were S-glutathionylated in a dose- and time-dependent manner following treatment of mice with drugs that alter reactive oxygen or nitrogen species. Tandem mass spectrometry analyses identified Cys(256) of serpin A1 and Cys(263) of serpin A3 as the S-glutathionylated residues. In human plasma from cancer patients, there were higher levels of unmodified serpin A1 and A3, but following treatments with redox active drugs, relative S-glutathionylation of these serpins was higher in plasma from normal individuals. There is potential for S-glutathionylated serpins A1 and A3 to act as pharmacodynamic biomarkers for evaluation of patient response to drugs that target redox pathways.

Topics: alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; Animals; Biomarkers, Tumor; Cisplatin; Dose-Response Relationship, Drug; Drug Combinations; Glutathione; Glutathione Disulfide; Humans; Immunoprecipitation; Mice; Neoplasms; Oxidation-Reduction; Serpins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry