Abstract 1615: The redox modulator NOV-002 inhibits proliferation of ovarian tumor cells but increases proliferation of myeloid cells
Authors: Bowers Robert , Townsend Danyelle M. , Manevich Yefim , Pazoles Christopher J. , Tew Kenneth D. 
Published: February 2011

Abstract
Clinical trials in solid tumor indications have shown that NOV-002 (a formulation of glutathione disulfide) combined with standard chemotherapeutic regimens results in increased efficacy and improved tolerance of standard chemotherapy (e.g. enhanced hematological recovery, immune stimulation). Non-clinical studies have interrogated the myeloproliferative and antitumor activity of the drug. NOV-002 alters redox homeostasis, at the cell surface and intracellularly, through kinase signaling culminating in differential effects on cell proliferation/survival in myeloid verses tumor cells. Thus, we previously showed that NOV-002 has positive growth effects on human myeloid lineage cells (HL60) and yet the drug leads to cell cycle arrest and apoptosis in human ovarian (SKOV3) cancer cells. In the present study, we sought to understand differences in redox-mediated signaling events that govern the opposing pharmacological properties of NOV-002. While the redox-signaling events are quite similar, the cellular consequences are distinct. Chronic treatment of cells with NOV-002 leads to enhanced proliferation in HL60 cells and growth arrest in SKOV3 cells. The alteration in growth rate occurs in both myeloid and tumor cell types in parallel with stress-induced S-glutathionylation and activation of MAP kinase pathways. In myeloid lineage cells, activation of MAP- and JAK/STAT-kinases leads to proliferation whereas activation of this pathway in SKOV3 cells leads to apoptosis. NOV-002 treatment also results in changes in plasma and mitochondrial membrane potentials in both cell models. These changes were concurrent with time- and dose-dependent increases in the accumulation of intracellular Ca2+. Interestingly, dose- and time- dependent increases in nitric oxide (NO) generation were observed in HL60 cells and shown to be mediated through eNOS. SKOV 3 cells do not express eNOS and, consequently, NO generation was not detected. Finally, redox-modulation of cell surface thiols (via S-glutathionylation) occurs in both cell types but to different extents. NOV-002 treatment leads to a ∼75% decrease in free sulfhydryls in myeloid cells whereas ovarian cancer cell surface free sulfhydryls were reduced by only ∼5%. It remains to be determined whether these observed differences in cell surface protein glutathionylation and/or in mechanism of Ca2+ flux can be linked to the opposite effects of NOV-002 on proliferation/survival in myeloid and tumor cells. Regardless of the basis of this difference, it can be speculated that the differential effects of NOV-002 on myeloid and tumor cells in vitro may relate to the unique clinical profile that NOV-002 has demonstrated to date– increased survival and anti-tumor efficacy combined with mitigation of chemotherapy-induced hematological toxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1615.