Abstract C109: NOV-002 suppresses tumor cell growth by modulating redox-sensitive cell signaling

Abstract

Abstract Regulation of cell proliferation/survival is complex, impacted by multiple endogenous and exogenous stimuli capable of triggering overlapping and competing signaling pathways whose net effects can be quite cell dependent. Changes in redox status is one regulator of cell life/death decisions under both physiologic and pathologic conditions. Here we report on the anti-proliferative effects of a pharmacologically generated oxidative signal in human tumor cells using NOV-002, a glutathione disulfide-mimetic in advanced clinical trials for oncological indications. NOV-002 has demonstrated efficacy (increased survival and/or decreased tumor growth) in non-small cell lung, breast and ovarian cancers when combined with standard chemotherapeutic agents. In addition, treatment with NOV-002 mitigates chemotherapy-associated hematological toxicity. Pre-clinical data has linked this effect to proliferation of bone marrow progenitor cells subsequent to generation of an oxidative signal, intracellularly and at the cell surface of myeloid lineage cells, leading to activation of multiple kinases known to regulate cell proliferation (e.g. MAP kinases, JAK/STAT kinases). The data presented here extend redox modulation studies with NOV-002 to tumor cells. SKOV3 cells (a human ovarian tumor cell line) were exposed to NOV-002 (250 uM). Within 5 min after a single treatment, cellular levels of reactive oxygen species (ROS) were significantly elevated indicating the generation of an oxidative signal by NOV-002. This was not, however, sufficient to influence redox-sensitive cell signaling or tumor cell proliferation rate. In contrast, more prolonged exposure to NOV-002 (daily treatment for 5 days) resulted in a sustained elevation in ROS and dose-dependent activation of the proliferation-regulating MAP kinase, JNK, as evidenced by an increase in its active, phosphorylated form. Most importantly, this redox-activated cell signaling effect was associated with a significantly decreased proliferation rate of the SKOV3 cells that persisted even after stopping treatment with NOV-002. Thus, oxidative signal generation and MAP kinase pathway activation by NOV-002 appears to result in cell-type dependent effects on proliferation/survival. In myeloid lineage/bone marrow cells, chronic exposure to NOV-002 leads to increased proliferation while in tumor cells the result is a decrease in proliferation. These dichotomous effects may contribute to the unique clinical profile that NOV-002 has demonstrated to date — increased anti-tumor efficacy and survival combined with enhanced recovery from chemotherapy-induced hematological toxicity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C109.