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• W1438762488 abstract "AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA3339 Constitutively elevated levels of cellular oxidative stress and dependence on mitogenic and anti-apoptotic reactive oxygen species (ROS)-signaling represent a specific vulnerability of malignant cells that can be selectively targeted by novel prooxidant redox chemotherapeutics. Here, we demonstrate that phenothiazinium-based redox cyclers (PRC-compounds) induce selective cancer cell apoptosis by NAD(P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds derived from methylene blue against human metastatic melanoma cell lines, apoptosis occurred with phosphatidylserine-externalization, loss of mitochondrial transmembrane potential, cytochrome C release, caspase-3 activation, and massive ROS production. Remarkably, PRC-apoptogenicity against G361 human metastatic melanoma cells was suppressed using the NQO1-inhibitor dicoumarol. The critical role of NQO1 in PRC-apoptogenicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT15) stably overexpressing active NQO1 displayed strongly enhanced PRC-sensitivity as compared to vector-control transfected cells with base line NQO1 activity. NQO1 is an antioxidant defense enzyme, and constitutive NQO1 overexpression leading to high specific enzymatic activity is associated with various human malignancies including melanoma, non-small-cell lung carcinoma, pancreas carcinoma, and breast and colon adenocarcinoma. The emerging role of overexpression of NQO1 in redox dysregulation of various human tumors resulting from Keap1 gene point mutations suggests feasibility of selecting NQO1-activated PRC lead compounds as tumor-selective bioreductive chemotherapeutics based on prior tumor genotyping. Moreover, a second class of quinone-based redox cyclers (QRC-compounds) has been identified that induces preferential cancer cell apoptosis by prooxidant mechanisms without dependence on NQO1-bioreductive activation. RT-PCR array expression analysis using the Human Stress and Toxicity PathwayFinder (Superarray) followed by immunoblot confirmation suggests that in human A375 melanoma cells, the redox cycler QRC-26 strongly upregulates heme oxygenase-1 (HO-1) and heat shock protein 70B’ (Hsp70B’), an Hsp70 subtype induced only under conditions of extreme cellular stress. Feasibility of therapeutic intervention using QRC-26 has been demonstrated in a human A375 melanoma mouse xenograft model. Future research will test the hypothesis that redox phenotyping and genotyping may guide the selection of PRC and QRC redox chemotherapeutics that efficiently target the NQO1-redox Achilles heel of the individual tumor. Supported in part by grants from NIH (R01CA122484; ES06694), ABRC (0721), and NSF (DGE-0114420)." @default.
• W1438762488 created "2016-06-24" @default.
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• W1438762488 date "2008-05-01" @default.
• W1438762488 modified "2023-09-27" @default.
• W1438762488 title "Targeting the NQO1-redox Achilles heel of cancer using small molecule prooxidant redox cyclers." @default.
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