**3.1 Initial discovery of β-lapachone's effect on DNA repair**

In the late 1980s, our laboratory began searching for DNA repair modulators that synergize with ionizing radiation to kill cancer cells more effectively. The goal was to thwart cancer cells' ability to repair IR damage, to avoid the survival of IR-resistant malignant cells that have undergone potentially lethal damage repair (PLDR). One of those compounds was (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2 b]pyran-5,6-dione), also known as β-lapachone [9].

We found that just four micromolar β-lapachone inhibited single-strand DNA break repair in cancer cells exposed to DNA-damaging agent methyl methane sulfonate [9, 10], killing 99% of cells at an exposure time 90–120 min [11]. Additionally, we found that combining β-lapachone with ionizing radiation in Hep2 cells increased double-strand breaks and dramatically lowered the dose of radiation required for cell death, highlighting β-lapachone as a potent radiosensitizer [12].

In the 1990s and early 2000s, we conducted subtraction-hybridization screening to isolate X-ray inducible genes to investigate ionizing radiation resistance and found Xip3, also known as NQO1 [13]. Dicoumarol, an NQO1 inhibitor, specifically blocked β-lapachone's toxicity, indicating that the radiosensitizer may be bioactivated by this enzyme. As NQO1 is specifically expressed in tumor cells, this indicated a promising use of β-lapachone as a cancer therapeutic with or without ionizing radiation.
