Ferrocenes as new anticancer drug candidates: Determination of the mechanism of action

Eur J Pharmacol. 2020 Jan 15;867:172825. doi: 10.1016/j.ejphar.2019.172825. Epub 2019 Nov 23.


Chemotherapy plays an essential role in the management of cancer worldwide. However, it is a non-specific treatment limited by major drawbacks, thus identification and testing of new promising molecular structures representing potential drug candidates are urgently needed. In this work, ferrocene complexes as potential antitumor drugs that display cytotoxicity in low micromolar concentrations against ovarian cancer cells A2780 and SK-OV-3 were investigated to identify their mode of action. Their mechanism of cellular accumulation was studied using differential pulse voltammetry and inductively coupled plasma - mass spectrometry. Their mode of cell death induction was determined by changes in the mitochondrial membrane potential, production of reactive oxygen species and by Annexin V staining. Transferrin receptors were identified as key mediators of intracellular accumulation of ferrocenes and the extent of cellular uptake reflected the anticancer activity of individual compounds. Functional analysis revealed activation of intrinsic apoptosis as a dominant mechanism leading to regulated cell death induced in ovarian cancer cells by ferrocenes. Ferrocenes represent a group of promising sandwich organometallic complexes exerting cytotoxic activity. We suggest their application not only as standalone chemotherapeutics but also as modifying substituents of known drugs to improve their antitumor effects.

Keywords: Cellular uptake; Ferrocene; Ovarian cancer; Reactive oxygen species; Transferrin; Transferrin receptor.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Female
  • Ferrous Compounds / pharmacology*
  • Ferrous Compounds / therapeutic use
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Metallocenes / pharmacology*
  • Metallocenes / therapeutic use
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Reactive Oxygen Species / metabolism
  • Receptors, Transferrin / metabolism


  • Antineoplastic Agents
  • Ferrous Compounds
  • Metallocenes
  • Reactive Oxygen Species
  • Receptors, Transferrin
  • ferrocene