Journal article
Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers
Molecular cancer therapeutics, Vol.12(10), pp.2110-2120
10/2013
DOI: 10.1158/1535-7163.MCT-12-0962
PMCID: PMC3807805
PMID: 23883585
Abstract
Improving patient outcome by personalized therapy involves a thorough
understanding of an agent’s mechanism of action. β-Lapachone
(clinical forms, Arq501/Arq761) has been developed to exploit dramatic
cancer-specific elevations in the phase II detoxifying enzyme, NAD(P)H:quinone
oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including
primary and metastatic (e.g., triple-negative (ER-, PR-, Her2/Neu-)) breast
cancers. To define cellular factors that influence the efficacy of
β-lapachone using knowledge of its mechanism of action, we confirmed
that NQO1 was required for lethality and mediated a futile redox cycle where
~120 moles of superoxide were formed per mole of β-lapachone in
5 min. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA
single strand break-dependent PARP1 hyperactivation, caused dramatic loss of
essential nucleotides (NAD+/ATP) and elicited programmed necrosis in breast
cancer cells. While PARP1 hyperactivation and NQO1 expression were major
determinants of β-lapachone-induced lethality, alterations in catalase
expression, including treatment with exogenous enzyme, caused marked
cytoprotection. Thus, catalase is an important resistance factor, and highlights
H
2
O
2
as an obligate ROS for cell death from this
agent. Exogenous superoxide dismutase (SOD) enhanced catalase-induced
cytoprotection. β-Lapachone-induced cell death included AIF
translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1
cleavage, and GAPDH S-nitrosylation, which were abrogated by catalase. We
predict that the ratio of NQO1:catalase activities in breast cancer versus
associated normal tissue are likely to be the major determinants affecting the
therapeutic window of β-lapachone and other NQO1 bioactivatable
drugs.
Details
- Title: Subtitle
- Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers
- Creators
- Erik A Bey - Department of Basic Pharmaceutical Sciences, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506Kathryn E Reinicke - Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106Melissa C Srougi - Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106Marie Varnes - Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106Vernon Anderson - Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106John J Pink - Department of Oncology, Case Western Reserve University, Cleveland, Ohio 44106Long Shan Li - Department of Pharmacology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, UT Southwestern Medical Center at Dallas, TX 75390-8807Malina Patel - Department of Pharmacology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, UT Southwestern Medical Center at Dallas, TX 75390-8807Lifen Cao - Department of Pharmacology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, UT Southwestern Medical Center at Dallas, TX 75390-8807Zachary Moore - Department of Pharmacology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, UT Southwestern Medical Center at Dallas, TX 75390-8807Amy Rommel - Department of Pharmacology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, UT Southwestern Medical Center at Dallas, TX 75390-8807Michael Boatman - Department of Basic Pharmaceutical Sciences, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506Cheryl Lewis - Department of Surgery, UT Southwestern Medical Center at Dallas, TX 75390David M Euhus - Department of Surgery, UT Southwestern Medical Center at Dallas, TX 75390William G Bornmann - Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030Donald J Buchsbaum - Department of Radiation Oncology, University of Alabama-Birmingham, Birmingham, Alabama, 35233Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242Jinming Gao - Department of Pharmacology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, UT Southwestern Medical Center at Dallas, TX 75390-8807David A Boothman - Department of Pharmacology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, UT Southwestern Medical Center at Dallas, TX 75390-8807
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.12(10), pp.2110-2120
- DOI
- 10.1158/1535-7163.MCT-12-0962
- PMID
- 23883585
- PMCID
- PMC3807805
- NLM abbreviation
- Mol Cancer Ther
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Grant note
- R01 CA102792 || CA / National Cancer Institute : NCI
- Language
- English
- Date published
- 10/2013
- Academic Unit
- Pathology; Radiation Oncology
- Record Identifier
- 9984047985002771
Metrics
23 Record Views