Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers

Erik A. Bey, Kathryn E. Reinicke, Melissa C. Srougi, Marie Varnes, Vernon E. Anderson, John J. Pink, Long Shan Li, Malina Patel, Lifen Cao, Zachary Moore, Amy Rommel, Michael Boatman, Cheryl Lewis, David M Euhus, William G. Bornmann, Donald J. Buchsbaum, Douglas R. Spitz, Jinming Gao, David A. Boothman

Research output: Contribution to journalArticle

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., triplenegative (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 2 minutes. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA singlestrand break-dependent poly(ADP-ribose) polymerase-1 (PARP1) hyperactivation, caused dramatic loss of essential nucleotides (NAD + /ATP), and elicited programmed necrosis in breast cancer cells. Although 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 H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included apoptosis-inducing factor (AIF) translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and glyceraldehyde 3-phosphate dehydrogenase 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.

Original languageEnglish (US)
Pages (from-to)2110-2120
Number of pages11
JournalMolecular Cancer Therapeutics
Volume12
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Fingerprint

Catalase
Necrosis
Breast Neoplasms
Cytoprotection
NAD
Reactive Oxygen Species
Cell Death
Substrate Cycling
Apoptosis Inducing Factor
Glyceraldehyde-3-Phosphate Dehydrogenases
DNA Breaks
R Factors
In Situ Nick-End Labeling
Enzymes
Superoxides
Superoxide Dismutase
Oxidation-Reduction
Neoplasms
Mitochondria
Oxidoreductases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bey, E. A., Reinicke, K. E., Srougi, M. C., Varnes, M., Anderson, V. E., Pink, J. J., ... Boothman, D. A. (2013). Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers. Molecular Cancer Therapeutics, 12(10), 2110-2120. https://doi.org/10.1158/1535-7163.MCT-12-0962

Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers. / Bey, Erik A.; Reinicke, Kathryn E.; Srougi, Melissa C.; Varnes, Marie; Anderson, Vernon E.; Pink, John J.; Li, Long Shan; Patel, Malina; Cao, Lifen; Moore, Zachary; Rommel, Amy; Boatman, Michael; Lewis, Cheryl; Euhus, David M; Bornmann, William G.; Buchsbaum, Donald J.; Spitz, Douglas R.; Gao, Jinming; Boothman, David A.

In: Molecular Cancer Therapeutics, Vol. 12, No. 10, 10.2013, p. 2110-2120.

Research output: Contribution to journalArticle

Bey, EA, Reinicke, KE, Srougi, MC, Varnes, M, Anderson, VE, Pink, JJ, Li, LS, Patel, M, Cao, L, Moore, Z, Rommel, A, Boatman, M, Lewis, C, Euhus, DM, Bornmann, WG, Buchsbaum, DJ, Spitz, DR, Gao, J & Boothman, DA 2013, 'Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers', Molecular Cancer Therapeutics, vol. 12, no. 10, pp. 2110-2120. https://doi.org/10.1158/1535-7163.MCT-12-0962
Bey, Erik A. ; Reinicke, Kathryn E. ; Srougi, Melissa C. ; Varnes, Marie ; Anderson, Vernon E. ; Pink, John J. ; Li, Long Shan ; Patel, Malina ; Cao, Lifen ; Moore, Zachary ; Rommel, Amy ; Boatman, Michael ; Lewis, Cheryl ; Euhus, David M ; Bornmann, William G. ; Buchsbaum, Donald J. ; Spitz, Douglas R. ; Gao, Jinming ; Boothman, David A. / Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 10. pp. 2110-2120.
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