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 (HNCs). However, the 5-year overall survival rate for locally-advanced HNCs is ∼50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in many cancers, and β-lapachone (β-lap), an unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) levels that synergizes 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 ionizing radiation. 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 express 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-dependenttumor cell lethality, increased ROS, TUNEL positive cells, DNA damage, NAD+ and adenosine triphosphate (ATP) consumption, and resulted in significantantitumor 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.

Biological determinants of radioresistance and their remediation in pancreatic cancer

“…It has been demonstrated that targeting glutamine metabolism, using BPTES sensitizes PC cells to β-lap by enhancing reactive oxygen species as well as PARP activation, leading to enhanced tumor cell specific cytotoxicity [308]. β-lapachone has been shown to be a potential radiosensitizer in a variety of cancers [309,310]. …”

Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma

“…NADPH is also oxidized to NADP + by ribonucleotide reductase to maintain dNTP pools for DNA repair and cell survival following ionizing radiation (18). A synergistic effect is reported when combining sublethal doses of blapachone with radiation therapy in NQO1 + human prostate and head and neck cancers (7,8,34), as well as in non-small cell lung cancers (Boothman, pers. comm.).…”

“…Increased consumption of NAD + and ATP, enhanced DNA double-strand breaks, and prolongation of c-H2AX were attributed, in the combined therapy, to result in head and neck squamous cell carcinoma (HNSCC) tumor regression. The competition for NADPH as a substrate for futile redox cycling, reduction of antioxidant defense systems (thioredoxin and glutaredoxin), PARP activity, and as a cofactor for dNTP synthesis upon radiation and chemotherapeutic insult in high NQO1/CAT tumor cells results in selective cytotoxicity (34).…”

Reactive Oxygen Species Synergize To Potently and Selectively Induce Cancer Cell Death

“…In addition, while the work herein has focused on NSCLC, this drug combination is very likely to be effective in the many other cancer types with overexpression of NQO1, 27, 28 including pancreatic, 53 breast, 54 and head-and-neck cancers. 55 More generally, the potential of different ROS forms to synergize is intriguing and could be a general manner to exploit mechanism-based synergy to induce selective cancer cell death.…”