Efficacy of beta-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 £]-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. ?-lapachone decreased clonogenic cell survival, metabolic cell viability, and anchorage-independent growth in soft agar. The cytotoxic in vitro effects of ?- lapachone were inhibited with co-administration of dicumarol, a specific inhibitor of NQO1. In pre-established human pancreatic tumor xenografts in nude mice, ?-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.