Efficacy of beta-lapachone in pancreatic cancer treatment: exploiting the novel, therapeutic target NQO1.
NAD(P)H:quinone oxidoreductase (NQO1) is elevated in human pancreatic cancers. We hypothesized that beta-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. beta-lapachone decreased clonogenic cell survival, metabolic cell viability, and anchorage- independent growth in soft agar. The cytotoxic in vitro effects of beta-lapachone were inhibited with coadministration of dicumarol, a specific inhibitor of NQO1. In preestablished human pancreatic tumor xenografts in nude mice, beta-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.
Ough
Matthew
M
Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Lewis
Anne
A
Bey
Erik A
EA
Gao
Jinming
J
Ritchie
Justine M
JM
Bornmann
William
W
Boothman
David A
DA
Oberley
Larry W
LW
Cullen
Joseph J
JJ
D000368:Aged; D000818:Animals; D001682:Biological Availability; D003505:Cyclodextrins; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011379:Prognosis; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D003505:Cyclodextrins; D009285:Naphthoquinones; D018894:Reverse Transcriptase Inhibitors; C014638:beta-lapachone