Unusually marked hypoxic sensitization to indoloquinone EO9 and mitomycin C in a human colon-tumour cell line that lacks DT-diaphorase activity

Int J Cancer. 1994 Jan 2;56(1):134-9. doi: 10.1002/ijc.2910560124.

Abstract

Studies with purified DT-diaphorase have shown that the enzyme is capable of catalyzing a two-electron reduction of the novel indoloquinone EO9 to a DNA-damaging alkylating species. The aim of this study was to determine to what extent DT-diaphorase may be involved in the metabolic activation of EO9 and mitomycin C in both aerobic and hypoxic conditions. Two human colon-carcinoma cell lines were used; HT29 has high levels of DT-diaphorase whilst BE lacks this activity because of a point mutation in the NQOI gene. In aerobic conditions the 2 cell lines show similar sensitivities to a number of cytotoxic drugs including cisplatin, doxorubicin and etoposide. They are equally sensitive to the benzotriazine di-N-oxide SR 4233 but HT29 is more sensitive than BE to mitomycin C and EO9. Sensitivity to SR 4233 is increased by about 100-fold for both cell lines in hypoxic conditions. DT-diaphorase-deficient BE cells show markedly increased sensitivity to mitomycin C and particularly EO9 in hypoxic conditions, whereas DT-diaphorase-rich HT29 cells show little hypoxic sensitization to these agents unless exposed in the presence of dicoumarol. These results suggest that DT-diaphorase can reduce EO9 and mitomycin C to potent cytotoxic species in aerobic conditions, and this activity predominates over the one-electron-reducing enzymes even in hypoxic conditions. In the absence of DT-diaphorase activity, EO9 and mitomycin C are reduced in hypoxic conditions, presumably by one-electron-reducing enzymes, to a similar or greater extent than is achieved with DT-diaphorase.

Publication types

  • Comparative Study

MeSH terms

  • Aerobiosis / drug effects
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Agents / toxicity
  • Aziridines / therapeutic use*
  • Aziridines / toxicity
  • Cell Hypoxia / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Indolequinones*
  • Indoles / therapeutic use*
  • Indoles / toxicity
  • Mitomycin / therapeutic use*
  • Mitomycin / toxicity
  • NAD(P)H Dehydrogenase (Quinone) / deficiency*
  • NAD(P)H Dehydrogenase (Quinone) / drug effects
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology

Substances

  • Antineoplastic Agents
  • Aziridines
  • Indolequinones
  • Indoles
  • Mitomycin
  • NAD(P)H Dehydrogenase (Quinone)
  • apaziquone