naphthoquinones and 5-methoxy-1-2-dimethyl-3-((4-nitrophenoxy)methyl)indole-4-7-dione

Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (E

Topics: Antineoplastic Agents; Biosensing Techniques; Cell Line, Tumor; Cytosol; Dicumarol; Fluorescent Dyes; Glutaredoxins; Glutathione; Green Fluorescent Proteins; Humans; Indolequinones; Mitochondria; Molecular Imaging; Molecular Probes; Molecular Targeted Therapy; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Quinones; Reactive Oxygen Species; Substrate Specificity

Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by. quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16-F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16-F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ~80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16-F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells.

Topics: Activation, Metabolic; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Electron Transport Complex I; Enzyme Inhibitors; Humans; Indolequinones; Mice; Mitochondria; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasm Proteins; Neoplasms; Oxidation-Reduction; Prodrugs; Reactive Oxygen Species; Reverse Transcriptase Inhibitors; Rotenone