Journal article
Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors
Cancer Cell, Vol.30(6), pp.940-952
12/12/2016
DOI: 10.1016/j.ccell.2016.11.006
PMCID: PMC5161231
PMID: 27960087
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. [Display omitted] •Solid cancers overexpress NQO1, with low catalase levels, reverse of normal tissue•β-Lapachone kills independent of oncogenic driver or passenger mutations•Synergy with PARP inhibitors and β-lapachone is NQO1 dependent•PARP inhibitors + β-lap induce DNA lesions, block repair, and cause apoptosis Huang et al. show that combination treatment with NQO1 bioactivatible β-lapachone and a PARP inhibitor causes unrepaired DNA damage and induces apoptosis, and that the combination treatment has a synergistic therapeutic effect in orthotopic pancreatic and non-small-cell lung cancer models.
Details
- Title: Subtitle
- Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors
- Creators
- Xiumei Huang - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAEdward A Motea - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAZachary R Moore - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAJun Yao - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAYing Dong - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAGaurab Chakrabarti - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAJessica A Kilgore - Department of Biochemistry, SCCC, UTSW, Dallas, TX 75390, USAMolly A Silvers - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAPraveen L Patidar - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAAgnieszka Cholka - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAFarjana Fattah - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USAYoonjeong Cha - Immuneering Corporation, One Broadway 14th Floor, Cambridge, MA 02142, USAGlenda G Anderson - 5Degrees Bio., Inc., 111 North Market Street #300, San Jose, CA 95113, USARebecca Kusko - Immuneering Corporation, One Broadway 14th Floor, Cambridge, MA 02142, USAMichael Peyton - Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USAJingsheng Yan - Department of Biostatistics, UTSW, Dallas, TX 75390, USAXian-Jin Xie - Department of Biostatistics, UTSW, Dallas, TX 75390, USAVenetia Sarode - Department of Pathology, UTSW, Dallas, TX 75390, USANoelle S Williams - Department of Biochemistry, SCCC, UTSW, Dallas, TX 75390, USAJohn D Minna - Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USAMuhammad Beg - Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USADavid E Gerber - Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USAErik A Bey - Department of Pharmaceutical Sciences, West Virginia University Cancer Institute, Morgantown, WV 26506, USADavid A Boothman - Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA
- Resource Type
- Journal article
- Publication Details
- Cancer Cell, Vol.30(6), pp.940-952
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ccell.2016.11.006
- PMID
- 27960087
- PMCID
- PMC5161231
- ISSN
- 1535-6108
- eISSN
- 1878-3686
- Grant note
- name: UTSW SCCC, award: 5P30CA142543; name: Institute for Innovations in Medical Technology; DOI: 10.13039/100004917, name: CPRIT; DOI: 10.13039/100000054, name: NCI, award: CA102792; name: UTSW-MD Anderson SPORE, award: P50CA70907; name: AACR/PanCan, award: 12-60-25-BOOT, 15-65-25-BOOT; name: ArQule, Inc., award: SCCC-10Y11 ARQ-761, SCCC-15Y11
- Language
- English
- Date published
- 12/12/2016
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917778602771
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