Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of β-lapachone for pancreatic cancer therapy

Long Shan Li, Erik A. Bey, Ying Dong, Jieru Meng, Biswanath Patra, Jingsheng Yan, Xian Jin Xie, Rolf A. Brekken, Carlton C. Barnett, William G. Bornmann, Jinming Gao, David A. Boothman

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Abstract

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 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. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)275-285
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number2
DOIs
StatePublished - Jan 15 2011

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Pancreatic Neoplasms
NAD
Therapeutics
Reactive Oxygen Species
Single-Stranded DNA Breaks
Drug Compounding
Hemolytic Anemia
Standard of Care
Tumor Burden
Nude Mice
Small Interfering RNA
Neoplasms
Oxidoreductases
Cell Death
Research Design
Necrosis
Clone Cells
Adenosine Triphosphate
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of β-lapachone for pancreatic cancer therapy. / Li, Long Shan; Bey, Erik A.; Dong, Ying; Meng, Jieru; Patra, Biswanath; Yan, Jingsheng; Xie, Xian Jin; Brekken, Rolf A.; Barnett, Carlton C.; Bornmann, William G.; Gao, Jinming; Boothman, David A.

In: Clinical Cancer Research, Vol. 17, No. 2, 15.01.2011, p. 275-285.

Research output: Contribution to journalArticle

Li, Long Shan ; Bey, Erik A. ; Dong, Ying ; Meng, Jieru ; Patra, Biswanath ; Yan, Jingsheng ; Xie, Xian Jin ; Brekken, Rolf A. ; Barnett, Carlton C. ; Bornmann, William G. ; Gao, Jinming ; Boothman, David A. / Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of β-lapachone for pancreatic cancer therapy. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 2. pp. 275-285.
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AU - Li, Long Shan

AU - Bey, Erik A.

AU - Dong, Ying

AU - Meng, Jieru

AU - Patra, Biswanath

AU - Yan, Jingsheng

AU - Xie, Xian Jin

AU - Brekken, Rolf A.

AU - Barnett, Carlton C.

AU - Bornmann, William G.

AU - Gao, Jinming

AU - Boothman, David A.

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N2 - 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 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. Experimental Design: 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.

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