title: Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of β-lapachone for pancreatic cancer therapy.
abstract: OBJECTIVE
  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 β-lapachone (β-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.
  
  
  METHODS
  We examined the role of NAD(P)H:quinone oxidoreductase-1 (NQO1) in β-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 β-lap was determined using an optimal hydroxypropyl-β-cyclodextran (HPβ-CD) vehicle formulation in metastatic pancreatic cancer models.
  
  
  RESULTS
  β-Lap-mediated cell death required ∼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 β-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 β-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.
authors.affiliation: Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.
authors.forename: Long Shan
authors.initials: LS
authors.lastname: Li
authors.forename: Erik A
authors.initials: EA
authors.lastname: Bey
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.forename: Jieru
authors.initials: J
authors.lastname: Meng
authors.forename: Biswanath
authors.initials: B
authors.lastname: Patra
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Yan
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Carlton C
authors.initials: CC
authors.lastname: Barnett
authors.forename: William G
authors.initials: WG
authors.lastname: Bornmann
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human