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 language | English (US) |
|---|---|
| Pages (from-to) | 940-952 |
| Number of pages | 13 |
| Journal | Cancer Cell |
| Volume | 30 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 12 2016 |
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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
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 journal › Article
}
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 -