Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 43, Issue 2, Pages 178-190Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.03.035
Keywords
apoptosis; bioreductive activation; cancer; melanoma; methylene blue; NQO1; phenothiazinium redox cycler; redox chemotherapy; ROS; toluidine blue
Funding
- NCI NIH HHS [CA95060, P50 CA095060, P50 CA095060-04] Funding Source: Medline
- NIEHS NIH HHS [P30 ES006694-11A19006, P30 ES006694, ES06694] Funding Source: Medline
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Altered redox signaling and regulation in cancer cells represent a chemical vulnerability that can be targeted by selective chemotherapeutic intervention. Here, we demonstrate that 3,7-diaminophenothiazinium-based redox cyclers (PRC) induce selective cancer cell apoptosis by NAD(P) H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds including toluidine blue against human metastatic G361 melanoma cells, apoptosis occurred with phosphatidylserine externalization, loss of mitochondrial transmembrane potential, cytochrome c release, caspase-3 activation, and massive ROS production. Consistent with reductive activation and subsequent redox cycling as the mechanism of PRC cytotoxicity, coincubation with catalase achieved cell protection, whereas reductive antioxidants enhanced PRC cytotoxicity. Unexpectedly, human A375 melanoma cells were resistant to PRC-induced apoptosis, and PRC-sensitive G361 cells were protected by preincubation with the NQO1 inhibitor dicoumarol. Indeed, NQO1 specific enzymatic activity was 9-fold higher in G361 than in A375 cells. The critical role of NQO1 in PRC bioactivation and cytotoxicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT 15) stably overexpressing active NQO I displayed strongly enhanced PRC sensitivity as compared to vector control-transfected cells with baseline NQO1 activity. Based on the known overexpression of NQO1 in various tumors these findings suggest the feasibility of developing PRC lead compounds into tumor-selective bioreductive chemotherapeutics. (C) 2007 Elsevier Inc. All rights reserved.
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