Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent.

Abstract

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

NAD(P)H:

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.

• Authors: Jason Z Li, Yuebin Ke, Hara P Misra, Michael A Trush, Y Robert Li, Hong Zhu, Zhenquan Jia
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 281 Issue 3 Pg. 285-93 (Dec 15 2014) ISSN: 1096-0333 [Electronic] United States
• PMID: 25448047 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 5-methoxy-1,2-dimethyl-3-((4-nitrophenoxy)methyl)indole-4,7-dione
• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Indolequinones
• Naphthoquinones
• Neoplasm Proteins
• Prodrugs
• Reactive Oxygen Species
• Reverse Transcriptase Inhibitors
• Rotenone
• beta-lapachone
• NAD(P)H Dehydrogenase (Quinone)
• Electron Transport Complex I

Topics

• Activation, Metabolic (drug effects)
• Animals
• Antineoplastic Agents, Phytogenic (antagonists & inhibitors, metabolism, pharmacology)
• Cell Line, Tumor
• Electron Transport Complex I (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (pharmacology)
• Humans
• Indolequinones (pharmacology)
• Mice
• Mitochondria (drug effects, enzymology, metabolism)
• NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors, metabolism)
• Naphthoquinones (antagonists & inhibitors, metabolism, pharmacology)
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Neoplasms (drug therapy, enzymology, metabolism)
• Oxidation-Reduction (drug effects)
• Prodrugs (chemistry, metabolism, pharmacology)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Inhibitors (chemistry, metabolism, pharmacology)
• Rotenone (pharmacology)