Tumor-selective, futile redox cycle-induced bystander effects elicited by NQO1 bioactivatable radiosensitizing drugs in triple-negative breast cancers

Lifen Cao, Long Shan Li, Christopher Spruell, Ling Xiao, Gaurab Chakrabarti, Erik A. Bey, Kathryn E. Reinicke, Melissa C. Srougi, Zachary Moore, Ying Dong, Peggy Vo, Wareef Kabbani, Chin Rang Yang, Xiaoyu Wang, Farjana Fattah, Julio C. Morales, Edward A. Motea, William G. Bornmann, John S. Yordy, David A. Boothman

Research output: Contribution to journalReview article

21 Scopus citations

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 oxidoreductase 1 (NQO1). Since breast or other solid cancers have heterogeneous NQO1 expression, therapies that 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-lap treatment to elicit bystander effects, DNA damage, and cell death in neighboring NQO1 low cells. Results: β-Lap showed 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-lap treatment. β-Lap-treated NQO1+ cells died by programmed necrosis, whereas co-cultured NQO1- TNBC cells exhibited DNA damage and caspase-dependent apoptosis. NQO1 inhibition (dicoumarol) or H 2O2 scavenging (catalase [CAT]) blocked all responses. Only NQO1- cells neighboring NQO1+ TNBC cells responded to β-lap in vitro, and bystander effects correlated well with H 2O2 diffusion. Bystander effects in NQO1- cells in vivo within mixed 50:50 co-cultured xenografts were dramatic and depended on NQO1+ cells. However, normal human cells in vitro or in vivo did not show bystander effects, due to elevated endogenous CAT levels. Innovation and Conclusions: NQO1-dependent bystander effects elicited by NQO1 bioactivatable drugs (β-lap or deoxynyboquinone [DNQ]) likely contribute to their efficacies, killing NQO1+ solid cancer cells and eliminating surrounding heterogeneous NQO1low cancer cells. Normal cells/tissue are protected by low NQO1:CAT ratios. Antioxid. Redox Signal. 21, 237-250.

Original languageEnglish (US)
Pages (from-to)237-250
Number of pages14
JournalAntioxidants and Redox Signaling
Volume21
Issue number2
DOIs
StatePublished - Jul 10 2014

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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    Cao, L., Li, L. S., Spruell, C., Xiao, L., Chakrabarti, G., Bey, E. A., Reinicke, K. E., Srougi, M. C., Moore, Z., Dong, Y., Vo, P., Kabbani, W., Yang, C. R., Wang, X., Fattah, F., Morales, J. C., Motea, E. A., Bornmann, W. G., Yordy, J. S., & Boothman, D. A. (2014). Tumor-selective, futile redox cycle-induced bystander effects elicited by NQO1 bioactivatable radiosensitizing drugs in triple-negative breast cancers. Antioxidants and Redox Signaling, 21(2), 237-250. https://doi.org/10.1089/ars.2013.5462