NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer

Long-Shan Li; Srilakshmi Reddy; Zhen-Hua Lin; Shuangping Liu; Hyunsil Park; Stephen G Chun; William G Bornmann; Joel Thibodeaux; Jingsheng Yan; Gaurab Chakrabarti; Xian-Jin Xie; Baran D Sumer; David A Boothman; John S Yordy

doi:10.1158/1535-7163.MCT-15-0765

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NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer

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Peer reviewed

NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer

Long-Shan Li, Srilakshmi Reddy, Zhen-Hua Lin, Shuangping Liu, Hyunsil Park, Stephen G Chun, William G Bornmann, Joel Thibodeaux, Jingsheng Yan, Gaurab Chakrabarti, …

Molecular cancer therapeutics, Vol.15(7), pp.1757-1767

07/2016

DOI: 10.1158/1535-7163.MCT-15-0765

PMCID: PMC5123441

PMID: 27196777

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Abstract

Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR. Immunohistochemical staining and Western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs expressed elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL-positive cells, DNA damage, NAD(+), and ATP consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap-induced radiosensitization. Mol Cancer Ther; 15(7); 1757-67. ©2016 AACR.

Gene Expression

Reactive Oxygen Species - metabolism

Humans

Cell Survival - genetics

NAD(P)H Dehydrogenase (Quinone) - genetics

Head and Neck Neoplasms - metabolism

Cell Death - genetics

Adenosine Triphosphate - metabolism

Cell Death - drug effects

Gene Expression Regulation, Neoplastic - drug effects

Disease Models, Animal

Radiation, Ionizing

Catalase - genetics

Radiation-Sensitizing Agents - pharmacology

Head and Neck Neoplasms - drug therapy

Radiation Tolerance - genetics

Naphthoquinones - pharmacology

Cell Survival - radiation effects

Head and Neck Neoplasms - pathology

Catalase - metabolism

Xenograft Model Antitumor Assays

Animals

Survival Analysis

Cell Line, Tumor

NAD(P)H Dehydrogenase (Quinone) - metabolism

Head and Neck Neoplasms - genetics

Enzyme Activation

Details

Title: Subtitle: NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer
Creators: Long-Shan Li - The University of Texas Southwestern Medical Center
Srilakshmi Reddy - The University of Texas Southwestern Medical Center
Zhen-Hua Lin - Department of Pathology, Yanbian University Medical College, Yanji, Jilin, China
Shuangping Liu - Department of Pathology, Yanbian University Medical College, Yanji, Jilin, China
Hyunsil Park - The University of Texas Southwestern Medical Center
Stephen G Chun - Department of Radiation Oncology, MD Anderson Comprehensive Cancer Center, Houston, Texas
William G Bornmann - Department of Experimental Therapeutics, MD Anderson Comprehensive Cancer Center, Houston, Texas
Joel Thibodeaux - The University of Texas Southwestern Medical Center
Jingsheng Yan - The University of Texas Southwestern Medical Center
Gaurab Chakrabarti - The University of Texas Southwestern Medical Center
Xian-Jin Xie - Department of Clinical Sciences, University of Texas at Southwestern Medical Center, Dallas, Texas
Baran D Sumer - The University of Texas Southwestern Medical Center
David A Boothman - The University of Texas Southwestern Medical Center
John S Yordy - Anchorage and Valley Radiation Therapy Centers
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.15(7), pp.1757-1767
DOI: 10.1158/1535-7163.MCT-15-0765
PMID: 27196777
PMCID: PMC5123441
NLM abbreviation: Mol Cancer Ther
ISSN: 1535-7163
eISSN: 1538-8514
Publisher: United States
Grant note: P30 CA142543 / NCI NIH HHS R01 CA102792 / NCI NIH HHS
Language: English
Date published: 07/2016
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917661002771

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