High-Throughput Library Screening Identifies Two Novel NQO1 Inducers in Human Lung Cells

Abstract

Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element-mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)-specific gene expression-based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4'-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H(2)O(2) induced nuclear translocation of nuclear factor erythroid 2-related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES.

Resveratrol, Acetyl-Resveratrol, and Polydatin Exhibit Antigrowth Activity against 3D Cell Aggregates of the SKOV-3 and OVCAR-8 Ovarian Cancer Cell Lines

“…Acetyl-resveratrol has been shown to inhibit the cell cycle in established cancer cell lines and have synergistic actions with cytotoxic drugs [ 42 , 43 ]. At lower concentrations, it can increase the level of mRNA antioxidant proteins, suggesting that acetyl-resveratrol may act as a chemopreventive compound [ 12 ]. In a cell-free system, acetyl-resveratrol is converted back to resveratrol by the hydrolysis of the acetyl motif by intracellular esterases.…”

“…Because of the possibility of limited usefulness of resveratrol itself due to the low plasma concentrations, there is a need to investigate compounds that are related to resveratrol and that may have greater bioavailability after ingestion. Two possible candidate compounds are acetyl-resveratrol and polydatin, which are currently under investigation for their cancer preventative properties [ 12 , 13 ]. Polydatin has shown antitumour activities in in vitro studies [ 14 , 15 ].…”

The chemotherapeutic effects of lapacho tree extract: β-lapachone

“…Thus, the main task of increasing β-lapachone sensitivity is to raise the NQO1 level or activity in cancer cells. Recently some chemicals or many physical methods have been demonstrated to upregulate NQO1 level or increase NQO1 activity to enhance the cytotoxic effect of β-lapachone [17,[64][65][66][67]. In the chemical methods, many drugs including cisplatin [68], resveratrol [69,70], dimethyl fumarate [71], taxifolin [72], sulforaphane [73] etc.…”

Reduction of doxorubicin-induced genotoxicity by Handroanthus impetiginosus in mouse bone marrow revealed by micronucleus assay

“…However, it is also possible that β-lapachone induced a small number of DNA strand breaks owing to its ability to produce activated oxygen species (Docampo et al, 1979;Molina Portela and Stoppani, 1996;Molina Portela et al, 1996). β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b] pyran-5,6-dione, ARQ 501), a natural o-naphthoquinone and a major component in an ethanol extract of H. impetiginosus bark, displayed promising antitumor activity in various tumor cells (Pardee et al, 2002;Tagliarino et al, 2003;Terai et al, 2009;Tan et al, 2012) and has been tested as an antitumor drug in phase I, II, and III clinical trials in combination with other chemotherapeutic agents (Pardee et al, 2002;Bentle et al, 2007). The anticancer activity of β-lapachone may involve its catalysis by NAD(P) H:quinone oxidoreductase (NQO1, DT-diaphorase), which used NAD(P)H or NADH as an electron source to yield the two-electron reduction of β-lapachone (Pardee et al, 2002;Reinicke et al, 2005).…”

“…In addition, NQO1 has been shown to be an important factor in β-lapachone-induced cell death in many kinds of cancer cells (Pink et al, 2000;Reinicke et al, 2005), including breast cancer (Tagliarino et al, 2003), glioma (Park et al, 2011), and prostate cancer (Pink et al, 2000). In this context, other methods have been examined to increase NQO1 expression or activity in cancer cells (Terai et al, 2009;Tan et al, 2012;Satsu et al, 2012) in order to increase the clinical efficacy of β-lapachone. More recently, the genotoxic impact and genotoxic activities of the combination of β-lapachone and hydroxyurea (another anticancer drug and an inhibitor of ribonucleotide reductase) were reported in Allium cepa root meristem cells (Zabka et al, 2013).…”