title: NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer.
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.
authors.affiliation: Department of Radiation Oncology, University of Texas at Southwestern Medical Center, Dallas, Texas. Harold C. Simmons NCI Designated Comprehensive Cancer Center, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Long-Shan
authors.initials: LS
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, University of Texas at Southwestern Medical Center, Dallas, Texas. Harold C. Simmons NCI Designated Comprehensive Cancer Center, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Department of Pathology, Yanbian University Medical College, Yanji, Jilin, China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Lin
authors.affiliation: Department of Pathology, Yanbian University Medical College, Yanji, Jilin, China.
authors.forename: Shuangping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, University of Texas at Southwestern Medical Center, Dallas, Texas. Harold C. Simmons NCI Designated Comprehensive Cancer Center, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Hyunsil
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, MD Anderson Comprehensive Cancer Center, Houston, Texas.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Chun
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Comprehensive Cancer Center, Houston, Texas.
authors.forename: William G
authors.initials: WG
authors.lastname: Bornmann
authors.affiliation: Department of Pathology, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Joel
authors.initials: J
authors.lastname: Thibodeaux
authors.affiliation: Department of Clinical Sciences, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Radiation Oncology, University of Texas at Southwestern Medical Center, Dallas, Texas. Harold C. Simmons NCI Designated Comprehensive Cancer Center, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Gaurab
authors.initials: G
authors.lastname: Chakrabarti
authors.affiliation: Department of Clinical Sciences, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Harold C. Simmons NCI Designated Comprehensive Cancer Center, University of Texas at Southwestern Medical Center, Dallas, Texas. Department of Otolaryngology, Head and Neck Surgery, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: Baran D
authors.initials: BD
authors.lastname: Sumer
authors.affiliation: Department of Radiation Oncology, University of Texas at Southwestern Medical Center, Dallas, Texas. Harold C. Simmons NCI Designated Comprehensive Cancer Center, University of Texas at Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, University of Texas at Southwestern Medical Center, Dallas, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Valley Radiation Therapy Center, Palmer, Alaska. john.yordy@anchorageradiationtherapy.com.
authors.forename: John S
authors.initials: JS
authors.lastname: Yordy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D009285:Naphthoquinones; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; C014638:beta-lapachone; D000255:Adenosine Triphosphate; D002374:Catalase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human