@article{19a41512e7ad485b9bdb2a02d79212b9,
title = "Efficacy of β-lapachone in pancreatic cancer treatment: Exploiting the novel, therapeutic target NQO1",
abstract = "NAD(P)H:quinone oxidoreductase (NQO1) is elevated in human pancreatic cancers. We hypothesized that β-lapachone, a novel 1,2-naphthoquinone with potential antitumor activity in cancer cells expressing elevated levels of NQO1, would induce cytotoxicity in pancreatic cancer cells, wherein this two-electron reductase was recently found elevated, β-lapachone decreased clonogenic cell survival, metabolic cell viability, and anchorage-independent growth in soft agar. The cytotoxic in vitro effects of β-lapachone were inhibited with coadministration of dicumarol, a specific inhibitor of NQO1. In preestablished human pancreatic tumor xenografts in nude mice, β-lapachone demonstrated greater tumor growth inhibition when given intratumorally compared to when complexed with cyclodextrin to increase its bioavailability. Due to the poor prognosis of patients with pancreatic cancer and the limited effectiveness of surgery, chemotherapy, and radiation therapy, treatment regimens based on sound, tumor-specific rationales are desperately need for this disease.",
keywords = "B-lapachone, Cyclodextrins, NAD(P)H:quinone oxidoreductase, Pancreatic cancer, Quinones, Reactive oxygen species",
author = "Matthew Ough and Anne Lewis and Bey, {Erik A.} and Jinming Gao and Ritchie, {Justine M.} and William Bornmann and Boothman, {David A.} and Oberley, {Larry W.} and Cullen, {Joseph J.}",
note = "Funding Information: Pancreatic adenocarcinoma is now the fourth leading cause of cancer death in the United States with an overall 5-year survival rate of less than 5%.1 Even after curative resection, the 5-year survival rates achieved at specialized centers are less than 20% and the majority of patients die of metastatic cancer recurrence.2 Other adjuvant treatments such as radiation therapy and chemotherapy have not improved long-term survival after resection. β-lapachone is a natur.a lDly Ooc cOurring compound present in the bark of the South American Lapacho (Tabebuia avellanedae) tree. The compound has a number of antitumor, antiviral, and antitrypanosomal activities in vivo3-5 β-lapachone has significant antineo-plastic activity against a variety of human cancer cells, including breast, prostate, and lung cancers as well as promyelocytic leukemia cells.6 Previous studies demonstrated that the cytotoxic response of breast and prostate cancer cells to β-lapachone is significantly enhanced by the expression of NAD(P)H:quinone oxidoreductase (NQO1, E.C. 1.6.99.2),7 an enzyme that detoxifies quinones (e.g., β-lapachone, menadione), as well as serving as a protective mechanism against reactive oxygen species (ROS).6-9The NQO1-specific antitumor activity of β-lapachone in other cancer cells than breast or prostate have not been examined, and the universality of β-lapachone-mediated antitumor activity in other cancer cells has not been examined. ROS is initiated when reactive semi-quinones generate a redox cycle, resulting in superoxide (O2-) formation. NQO1 utilizes either NADH or NADPH as electron donors to catalyze the two-electron reduction of various quinones to hydroquinones. It is a direct reduction, and therefore, the unstable semiquinone intermediate is not formed, preventing reactive oxygen species formation. Reduction of β-lapachone by NQO1 leads to a futile cycling of the compound, wherein This work was supported by NIH grants DK the quinone and hydroquinone form a redox cycle with a net concomitant loss of reduced 60618, CA 66081, HL07485-24 and the Medical NAD(P)H.7",
year = "2005",
month = jan,
language = "English (US)",
volume = "4",
pages = "95--102",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Landes Bioscience",
number = "1",
}