Pulmonary carcinogenesis induced by ferric nitrilotriacetate in mice and protection from it by Brazilian propolis and artepillin C

Virchows Arch. 2001 Mar;438(3):259-70. doi: 10.1007/s004280000350.


In experiments using the renal carcinogen ferric nitrilotriacetate (Fe-NTA) in male ddY mice, primary pulmonary cancers were also induced in bronchiolar and alveolar tissues. 4-Hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), products of oxidative processes, increased in bronchiolar and alveolar cells after administration of Fe-NTA. These substances disappeared after oral administration of propolis or artepillin C, as shown histochemically, and correlated with an anticancer prophylactic effect of propolis and artepillin C. From our investigation, lipid peroxidation seems to play an important role in pulmonary carcinogenesis. Malignant progression from adenoma of bronchiolar or alveolar origin to malignant tumors has been proposed to involve a stepwise transformation. In our study, adenomas developed into adenocarcinomas and large cell carcinomas after treatment with Fe-NTA. In contrast, after oral administration of propolis or artepillin C, adenomas did not progress to carcinomas. Instead of developing into large cell cancers, as induced by Fe-NTA in control mice, adenomas showed remarkable proliferation of macrophages and local anti-oxidant activity after treatment with either propolis or artepillin C. Propolis and artepillin C therefore appear to inhibit lipid peroxidation and the development of pulmonary cancers.

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Aldehydes / analysis
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / analysis
  • Ferric Compounds / toxicity*
  • Immunohistochemistry
  • Lipid Peroxidation / drug effects
  • Lung Neoplasms / chemically induced*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Male
  • Mice
  • Nitrilotriacetic Acid / analogs & derivatives*
  • Nitrilotriacetic Acid / toxicity*
  • Nuclear Proteins / analysis
  • Phenylpropionates / pharmacology*
  • Proliferating Cell Nuclear Antigen / analysis
  • Propolis / pharmacology*
  • Thyroid Nuclear Factor 1
  • Transcription Factors / analysis


  • Aldehydes
  • Antineoplastic Agents
  • Ferric Compounds
  • Nuclear Proteins
  • Phenylpropionates
  • Proliferating Cell Nuclear Antigen
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • artepillin C
  • 8-Hydroxy-2'-Deoxyguanosine
  • Propolis
  • Deoxyguanosine
  • 4-hydroxy-2-nonenal
  • Nitrilotriacetic Acid
  • ferric nitrilotriacetate