Tumor-Selective, Futile Redox Cycle-Induced Bystander Effects Elicited by NQO1 Bioactivatable Radiosensitizing Drugs in Triple-Negative Breast Cancers

Abstract Aims: β-Lapachone (β- lap), a novel radiosensitizer with potent antitumor efficacy alone, selectively kills solid cancers that over-express NAD(P)H:quinone oxidoreductase1 (NQO1). Since breast or other solid cancers have heterogeneous NQO1 expression, therapiesthat reduce the resistance (e.g., NQO1low) of tumor cells will have significant clinical advantages. We tested whether NQO1-proficient (NQO1+) cells generated sufficient hydrogen peroxide (H2O2) after β- laptreatment to elicit bystander effects, DNA damage, and cell death in neighboring NQO1low cells. Results: β- Lapshowed NQO1-dependent efficacy against two triple-negative breast cancer(TNBC) xenografts. NQO1 expression variations in human breast cancer patient samples were noted, where ∼60% cancers over-expressed NQO1, with little or no expression in associated normal tissue. Differential DNA damage and lethality were noted in NQO1+ versus NQO1-deficient (NQO1−) TNBC cells and xenografts after β- laptreatment. β- Lap-treated NQO1+ cells ...