title: Tumor-selective, futile redox cycle-induced bystander effects elicited by NQO1 bioactivatable radiosensitizing drugs in triple-negative breast cancers.
abstract: OBJECTIVE
  β-Lapachone (β-lap), a novel radiosensitizer with potent antitumor efficacy alone, selectively kills solid cancers that over-express
  quinone oxidoreductase 1 (NQO1). Since breast or other solid cancers have heterogeneous NQO1 expression, therapies that reduce the resistance (e.g., NQO1(low)) 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 H2O2 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 H2O2 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 NQO1(low) cancer cells. Normal cells/tissue are protected by low NQO1:CAT ratios.
authors: 1 Department of General Surgery, The Second Xiangya Hospital of Central South University , Changsha, China .
authors: Lifen
authors: L
authors: Cao
authors: Long Shan
authors: LS
authors: Li
authors: Christopher
authors: C
authors: Spruell
authors: Ling
authors: L
authors: Xiao
authors: Gaurab
authors: G
authors: Chakrabarti
authors: Erik A
authors: EA
authors: Bey
authors: Kathryn E
authors: KE
authors: Reinicke
authors: Melissa C
authors: MC
authors: Srougi
authors: Zachary
authors: Z
authors: Moore
authors: Ying
authors: Y
authors: Dong
authors: Peggy
authors: P
authors: Vo
authors: Wareef
authors: W
authors: Kabbani
authors: Chin-Rang
authors: CR
authors: Yang
authors: Xiaoyu
authors: X
authors: Wang
authors: Farjana
authors: F
authors: Fattah
authors: Julio C
authors: JC
authors: Morales
authors: Edward A
authors: EA
authors: Motea
authors: William G
authors: WG
authors: Bornmann
authors: John S
authors: JS
authors: Yordy
authors: David A
authors: DA
authors: Boothman
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D009285:Naphthoquinones; D011809:Quinones; D011838:Radiation-Sensitizing Agents; C550580:deoxynyboquinone; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human