Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

Xiumei Huang, Edward A. Motea, Zachary R. Moore, Jun Yao, Ying Dong, Gaurab Chakrabarti, Jessica A. Kilgore, Molly A. Silvers, Praveen L. Patidar, Agnieszka Cholka, Farjana Fattah, Yoonjeong Cha, Glenda G. Anderson, Rebecca Kusko, Michael Peyton, Jingsheng Yan, Xian Jin Xie, Venetia Sarode, Noelle S. Williams, John D. MinnaMuhammad Beg, David E. Gerber, Erik A. Bey, David A. Boothman

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.

Original languageEnglish (US)
Pages (from-to)940-952
Number of pages13
JournalCancer Cell
Volume30
Issue number6
DOIs
StatePublished - Dec 12 2016

Keywords

  • ARQ761
  • NQO1
  • NQO1 bioctivatable drugs
  • NSCLC
  • Olaparib
  • PARP1
  • PDA
  • ROS
  • Rucaparib
  • combination chemotherapy
  • synthetic lethality
  • β-lapachone

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Huang, X., Motea, E. A., Moore, Z. R., Yao, J., Dong, Y., Chakrabarti, G., Kilgore, J. A., Silvers, M. A., Patidar, P. L., Cholka, A., Fattah, F., Cha, Y., Anderson, G. G., Kusko, R., Peyton, M., Yan, J., Xie, X. J., Sarode, V., Williams, N. S., ... Boothman, D. A. (2016). Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. Cancer Cell, 30(6), 940-952. https://doi.org/10.1016/j.ccell.2016.11.006