Journal article
NQO1-dependent, Tumor-selective Radiosensitization of Non-small Cell Lung Cancers
Clinical cancer research, Vol.25(8), pp.2601-2609
04/15/2019
DOI: 10.1158/1078-0432.CCR-18-2560
PMCID: PMC6788754
PMID: 30617135
Abstract
Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLC) is urgently needed. Here, we investigated the ability of β-lapachone (β-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1-3 Gy) in NSCLCs that overexpress NAD(P)H:Quinone Oxidoreductase 1 (NQO1).
The mechanism of lethality of low-dose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines
and validated in subcutaneous and orthotopic xenograft models
. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action.
β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD
/ATP levels, and increased double-strand break (DSB) lesions over time
. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 β-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (∼12 units) of any normal tissue. PK/PD responses confirm that IR + β-lap treatments hyperactivate PARP activity, greatly lower NAD
/ATP levels, and dramatically inhibit DSB repair in exposed NQO1
cancer tissue, whereas low NQO1 levels and high levels of catalase in associated normal tissue were protective.
Our data suggest that combination of sublethal doses of β-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + β-lap against patients with NQO1
NSCLCs.
Details
- Title: Subtitle
- NQO1-dependent, Tumor-selective Radiosensitization of Non-small Cell Lung Cancers
- Creators
- Edward A Motea - Indiana UniversityXiumei Huang - Indiana UniversityNaveen Singh - Indiana UniversityJessica A Kilgore - The University of Texas Southwestern Medical CenterNoelle S Williams - The University of Texas Southwestern Medical CenterXian-Jin Xie - Southwestern Medical CenterDavid E Gerber - The University of Texas Southwestern Medical CenterMuhammad S Beg - The University of Texas Southwestern Medical CenterErik A Bey - West Virginia UniversityDavid A Boothman - Indiana University
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.25(8), pp.2601-2609
- DOI
- 10.1158/1078-0432.CCR-18-2560
- PMID
- 30617135
- PMCID
- PMC6788754
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- K24 CA201543 / NCI NIH HHS R01 CA224493 / NCI NIH HHS P30 CA142543 / NCI NIH HHS
- Language
- English
- Date published
- 04/15/2019
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9984367736802771
Metrics
18 Record Views