Dihydrodiol dehydrogenases regulate the generation of reactive oxygen species and the development of cisplatin resistance in human ovarian carcinoma cells

Cancer Chemother Pharmacol. 2008 May;61(6):979-87. doi: 10.1007/s00280-007-0554-0. Epub 2007 Jul 28.


We have previously demonstrated that overexpression of dihydrodiol dehydrogenase isoform 1 (DDH1) or DDH2 leads to the induction of drug resistance to platinum based drugs in human ovarian, lung, cervical and germ cell tumor cell lines. DDH belongs to a family of aldoketo reductases that are involved in the detoxification of several endogenous and exogenous substrates. DDH1 and DDH2 in particular have been shown to be involved in the detoxification (activation?) of polycyclic aromatic hydrocarbons (PAH). Based on the involvement of DDH in the detoxification of electrophilic PAH intermediates, the effect of DDH on the production of reactive oxygen species (ROS) in a cisplatin-sensitive and -resistant human ovarian carcinoma cell line was investigated in the current study. In addition to the overexpression of DDH1 and DDH2, increased expression of DDH3 was demonstrated in the cisplatin-resistant 2008/C13* cells, compared to the parental 2008 cells. However, as assessed by RT-PCR, neither cell line expressed DDH4. The 2008/C13* cells were eightfold resistant to cisplatin, and transfection experiments utilizing cisplatin-sensitive 2008 cells suggest that this could be mediated by overexpression of either DDH1, DDH2, or DDH3. The 2008/C13* cells had lower basal intracellular ROS level as compared to the 2008 cells and ROS production was decreased in the recombinant 2008 cells with forced, constitutive overexpression of either, DDH1, DDH2, or DDH3. Transfection of siRNA against DDH1 or DDH2 in the cisplatin-resistant 2008/C13* cells not only significantly decreased their cisplatin-resistance index (as assayed by MTT and colony formation assay) but also led to an increase in the basal levels of ROS production (although transfection of siRNA against DDH3 resulted in cell death). The 2008/C13* cells were found to be cross-resistant to the cytotoxic effects of hydrogen peroxide and tert-butyl hydroperoxide and knockdown of either DDH1 or DDH2 expression (using siRNA) resulted in sensitization of the resistant cells to these agents. These results support the conclusion that the increased levels of DDH in the 2008/C13* cells are directly responsible for the reduced production of ROS and that this may play a role in the development of cisplatin resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Oxidoreductases / biosynthesis
  • Alcohol Oxidoreductases / physiology*
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Clone Cells
  • Drug Resistance, Neoplasm
  • Enzyme Induction / drug effects
  • Esterases / biosynthesis
  • Esterases / genetics
  • Female
  • Heme Oxygenase (Decyclizing) / biosynthesis
  • Heme Oxygenase (Decyclizing) / genetics
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Isoenzymes / biosynthesis
  • Isoenzymes / physiology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Oxidative Stress / drug effects
  • RNA, Small Interfering / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • tert-Butylhydroperoxide / pharmacology


  • Antineoplastic Agents
  • Isoenzymes
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • tert-Butylhydroperoxide
  • Hydrogen Peroxide
  • Alcohol Oxidoreductases
  • dihydrodiol dehydrogenases
  • Heme Oxygenase (Decyclizing)
  • heme oxygenase-2
  • Esterases
  • Cisplatin