Breast cancer affects 1 in every 8 U.S. women. Unfortunately, many current therapeutic approaches kill normal tissues in addition to cancerous tissues, thus limiting their clinical efficacy. NAD(P)H:quinone oxidoreductase 1(NQO1) is a detoxification enzyme expressed in high levels in a number of solid tumor tissues as well as cancer cell lines including those of the breast, prostate, head and neck, and non-small cell lung carcinomas. Two novel quinones β-lapachone (β-lap) and isobutyl-deoxynyboquinone (IB-DNQ) have been found to be toxic in cells with elevated NQO1 levels. NQO1 reduces both β-lap or IB-DNQ to a highly unstable hydroquinone, which then oxidizes back to the parent compound via formation of a semiquinone intermediate, thus creating a futile redox cycle and generating reactive oxygen species (ROS). Of interest, a subset of breast cancers harbor BRCA1/2-mutations, which are some of the hardest to treat tumors, also express high levels of NQO1. We therefore hypothesize that BRCA1-mutant breast cancers expressing NQO1 will be exquisitively sensitive to β-lap or IB-DNQ. Our data demonstrate that NQO1 expressing BRCA1-mutant breast cancer cells are sensitive to both β-lap and IB-DNQ-induced cell death. Cell death can be prevented upon treatment with the NQO1 inhibitor, dicoumarol. Furthermore, we demonstrate that the NQO1-mediated metabolism of β-lap or IB-DNQ causes DNA damage. These results suggest that β-lap and IB-DNQ are effective selective therapies for NQO1 expressing, BRCA1-mutant cancers.

Elucidation of the efficacy of the antitumor quinones, isobutyl-deoxynyboquinone and beta-lapachone in a BRCA1-mutant breast cancer cell line expressing elevated NQO1 levels

2019 Spring National Meeting

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