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

25 Citations (Scopus)

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

Fingerprint

Pharmaceutical Preparations
Neoplasms
Poly(ADP-ribose) Polymerases
Recycling
Caspases
Pancreatic Neoplasms
Heterografts
Oxygen Consumption
Non-Small Cell Lung Carcinoma
DNA Repair
NAD
Oxidation-Reduction
Reactive Oxygen Species
Cell Death
Necrosis
Apoptosis
Breast Neoplasms
Lung
Survival
Poly(ADP-ribose) Polymerase Inhibitors

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Huang, X., Motea, E. A., Moore, Z. R., Yao, J., Dong, Y., Chakrabarti, G., ... 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

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. / Huang, Xiumei; Motea, Edward A.; Moore, Zachary R.; Yao, Jun; Dong, Ying; Chakrabarti, Gaurab; Kilgore, Jessica A.; Silvers, Molly A.; Patidar, Praveen L.; Cholka, Agnieszka; Fattah, Farjana; Cha, Yoonjeong; Anderson, Glenda G.; Kusko, Rebecca; Peyton, Michael; Yan, Jingsheng; Xie, Xian Jin; Sarode, Venetia; Williams, Noelle S.; Minna, John D.; Beg, Muhammad; Gerber, David E.; Bey, Erik A.; Boothman, David A.

In: Cancer Cell, Vol. 30, No. 6, 12.12.2016, p. 940-952.

Research output: Contribution to journalArticle

Huang, X, Motea, EA, Moore, ZR, Yao, J, Dong, Y, Chakrabarti, G, Kilgore, JA, Silvers, MA, Patidar, PL, Cholka, A, Fattah, F, Cha, Y, Anderson, GG, Kusko, R, Peyton, M, Yan, J, Xie, XJ, Sarode, V, Williams, NS, Minna, JD, Beg, M, Gerber, DE, Bey, EA & Boothman, DA 2016, 'Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors', Cancer Cell, vol. 30, no. 6, pp. 940-952. https://doi.org/10.1016/j.ccell.2016.11.006
Huang, Xiumei ; Motea, Edward A. ; Moore, Zachary R. ; Yao, Jun ; Dong, Ying ; Chakrabarti, Gaurab ; Kilgore, Jessica A. ; Silvers, Molly A. ; Patidar, Praveen L. ; Cholka, Agnieszka ; Fattah, Farjana ; Cha, Yoonjeong ; Anderson, Glenda G. ; Kusko, Rebecca ; Peyton, Michael ; Yan, Jingsheng ; Xie, Xian Jin ; Sarode, Venetia ; Williams, Noelle S. ; Minna, John D. ; Beg, Muhammad ; Gerber, David E. ; Bey, Erik A. ; Boothman, David A. / Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. In: Cancer Cell. 2016 ; Vol. 30, No. 6. pp. 940-952.
@article{81e0c0b740054ac6ba333d7ac37b6b96,
title = "Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors",
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.",
keywords = "ARQ761, combination chemotherapy, NQO1, NQO1 bioctivatable drugs, NSCLC, Olaparib, PARP1, PDA, ROS, Rucaparib, synthetic lethality, β-lapachone",
author = "Xiumei Huang and Motea, {Edward A.} and Moore, {Zachary R.} and Jun Yao and Ying Dong and Gaurab Chakrabarti and Kilgore, {Jessica A.} and Silvers, {Molly A.} and Patidar, {Praveen L.} and Agnieszka Cholka and Farjana Fattah and Yoonjeong Cha and Anderson, {Glenda G.} and Rebecca Kusko and Michael Peyton and Jingsheng Yan and Xie, {Xian Jin} and Venetia Sarode and Williams, {Noelle S.} and Minna, {John D.} and Muhammad Beg and Gerber, {David E.} and Bey, {Erik A.} and Boothman, {David A.}",
year = "2016",
month = "12",
day = "12",
doi = "10.1016/j.ccell.2016.11.006",
language = "English (US)",
volume = "30",
pages = "940--952",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

AU - Huang, Xiumei

AU - Motea, Edward A.

AU - Moore, Zachary R.

AU - Yao, Jun

AU - Dong, Ying

AU - Chakrabarti, Gaurab

AU - Kilgore, Jessica A.

AU - Silvers, Molly A.

AU - Patidar, Praveen L.

AU - Cholka, Agnieszka

AU - Fattah, Farjana

AU - Cha, Yoonjeong

AU - Anderson, Glenda G.

AU - Kusko, Rebecca

AU - Peyton, Michael

AU - Yan, Jingsheng

AU - Xie, Xian Jin

AU - Sarode, Venetia

AU - Williams, Noelle S.

AU - Minna, John D.

AU - Beg, Muhammad

AU - Gerber, David E.

AU - Bey, Erik A.

AU - Boothman, David A.

PY - 2016/12/12

Y1 - 2016/12/12

N2 - 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.

AB - 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.

KW - ARQ761

KW - combination chemotherapy

KW - NQO1

KW - NQO1 bioctivatable drugs

KW - NSCLC

KW - Olaparib

KW - PARP1

KW - PDA

KW - ROS

KW - Rucaparib

KW - synthetic lethality

KW - β-lapachone

UR - http://www.scopus.com/inward/record.url?scp=85004147144&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85004147144&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.11.006

DO - 10.1016/j.ccell.2016.11.006

M3 - Article

C2 - 27960087

AN - SCOPUS:85004147144

VL - 30

SP - 940

EP - 952

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 6

ER -