Modulating Endogenous NQO1 Levels Identifies Key Regulatory Mechanisms of Action of β-Lapachone for Pancreatic Cancer Therapy

Purpose: Pancreatic cancer is the fourth leading cause of cancer-related deaths, in which the 5-year survival rate is less than 5%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Although prior work suggested that beta-lapachone (beta-lap) could be used for the treatment of pancreatic cancers, the lack of knowledge of the compound's mechanism of action prevented optimal use of this agent. Experimental Design: We examined the role of NAD(P) H: quinone oxidoreductase-1 (NQO1) in beta-lap-mediated antitumor activity, using a series of MIA PaCa-2 pancreatic cancer clones varying in NQO1 levels by stable shRNA knockdown. The antitumor efficacy of beta-lap was determined using an optimal hydroxypropyl-beta-cyclodextran (HP beta-CD) vehicle formulation in metastatic pancreatic cancer models. Results: beta-Lap-mediated cell death required similar to 90 enzymatic units of NQO1. Essential downstream mediators of lethality were as follows: (i) reactive oxygen species (ROS); (ii) single-strand DNA breaks induced by ROS; (iii) poly(ADP-ribose) polymerase-1 (PARP1) hyperactivation; (iv) dramatic NAD(+)/ATP depletion; and (v) programmed necrosis. We showed that 1 regimen of beta-lap therapy (5 treatments every other day) efficaciously regressed and reduced human pancreatic tumor burden and dramatically extended the survival of athymic mice, using metastatic pancreatic cancer models. Conclusions: Because NQO1 enzyme activities are easily measured and commonly overexpressed (i. e., >70%) in pancreatic cancers 5- to 10-fold above normal tissue, strategies using beta-lap to efficaciously treat pancreatic cancers are indicated. On the basis of optimal drug formulation and efficacious antitumor efficacy, such a therapy should be extremely safe and not accompanied with normal tissue toxicity or hemolytic anemia. Clin Cancer Res; 17(2); 275-85. (C)2011 AACR.