NQO1 bioactivatable drugs enhance radiation responses

Erik A. Bey, Julia C. Meade, Molly A. Silvers, Edward A. Motea, Praveen L. Patidar, Rolf Brekken, Stanislaw Deja, Matthew E. Merritt, Jessica A. Kilgore, Yuliang Liu, Xiumei Huang, Longshan Li, John Yordy, Noelle S. Williams, Jinming Gao, David A. Boothman

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

Abstract

Inhibitors of cancer-specific pathways can selectively kill off tumor cells. However, heterogeneity of neoplastic tissue often allows other cancer cells to repopulate the tissue area, leading to regeneration of resistant disease. β-Lapachone is a novel bioactivatable drug that relies specifically on tumor-directed upregulated levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) to kill most solid cancers, such as 90 % of pancreatic and non-small cell lung, 60 % of breast, colon, and prostate, as well as 50 % of head and neck cancers. Once β-lapachone is bioactivated by the NQO1 enzyme, massive levels of hydrogen peroxide are produced that, in turn, damage the DNA of cancer cells, while associated normal tissues, which lack NQO1, are protected by high levels of catalase. If tumors are irradiated prior to applying β-lapachone, the drug (clinical form, ARQ761) can work in combination with the vast spectrum of DNA lesions created by ionizing radiation, particularly DNA base lesions, single and double strand breaks (SSBs and DSBs), in addition to the mas-sive hydrogen peroxide-based lesions created by β-lapachone, to cause tumordependent poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Once tumor-selective PARP hyperactivation is induced in cancer cells, they die due to low concomitant catalase levels. In contrast, associated normal tissue, as well as other normal tissue, lack elevated levels of NQO1 and have high catalase levels. Cancer cell death ultimately occurs by NAD + -depletion, where resistance to NQO1 bioactivatable drugs has not been noted to date. Current studies are focused on pancreatic and non-small cell lung cancers, as NQO1 is elevated in nearly all of these cancers.

Original languageEnglish (US)
Title of host publicationStrategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment
PublisherSpringer International Publishing
Pages225-252
Number of pages28
ISBN (Electronic)9783319455945
ISBN (Print)9783319455921
DOIs
StatePublished - Jan 1 2016

Fingerprint

Radiation
Pharmaceutical Preparations
Neoplasms
Catalase
NAD
Hydrogen Peroxide
DNA
Head and Neck Neoplasms
Ionizing Radiation
Non-Small Cell Lung Carcinoma
DNA Damage
Prostate
Regeneration
Oxidoreductases
Colon
Breast
Cell Death
Lung
Enzymes

Keywords

  • NAD -Keresis
  • NAD loss
  • NQO1 expression
  • Oxidative stress
  • PARP hyperactivation
  • Tumorselectivity

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bey, E. A., Meade, J. C., Silvers, M. A., Motea, E. A., Patidar, P. L., Brekken, R., ... Boothman, D. A. (2016). NQO1 bioactivatable drugs enhance radiation responses. In Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment (pp. 225-252). Springer International Publishing. https://doi.org/10.1007/978-3-319-45594-5_10

NQO1 bioactivatable drugs enhance radiation responses. / Bey, Erik A.; Meade, Julia C.; Silvers, Molly A.; Motea, Edward A.; Patidar, Praveen L.; Brekken, Rolf; Deja, Stanislaw; Merritt, Matthew E.; Kilgore, Jessica A.; Liu, Yuliang; Huang, Xiumei; Li, Longshan; Yordy, John; Williams, Noelle S.; Gao, Jinming; Boothman, David A.

Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment. Springer International Publishing, 2016. p. 225-252.

Research output: Chapter in Book/Report/Conference proceedingChapter

Bey, EA, Meade, JC, Silvers, MA, Motea, EA, Patidar, PL, Brekken, R, Deja, S, Merritt, ME, Kilgore, JA, Liu, Y, Huang, X, Li, L, Yordy, J, Williams, NS, Gao, J & Boothman, DA 2016, NQO1 bioactivatable drugs enhance radiation responses. in Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment. Springer International Publishing, pp. 225-252. https://doi.org/10.1007/978-3-319-45594-5_10
Bey EA, Meade JC, Silvers MA, Motea EA, Patidar PL, Brekken R et al. NQO1 bioactivatable drugs enhance radiation responses. In Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment. Springer International Publishing. 2016. p. 225-252 https://doi.org/10.1007/978-3-319-45594-5_10
Bey, Erik A. ; Meade, Julia C. ; Silvers, Molly A. ; Motea, Edward A. ; Patidar, Praveen L. ; Brekken, Rolf ; Deja, Stanislaw ; Merritt, Matthew E. ; Kilgore, Jessica A. ; Liu, Yuliang ; Huang, Xiumei ; Li, Longshan ; Yordy, John ; Williams, Noelle S. ; Gao, Jinming ; Boothman, David A. / NQO1 bioactivatable drugs enhance radiation responses. Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment. Springer International Publishing, 2016. pp. 225-252
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