The Cytotoxic Effect of Newly Synthesized Ferrocenes against Cervical Carcinoma Cells Alone and in Combination with Radiotherapy

Abstract

Cervical cancer is one of the most common types of cancer in women, with approximately 500,000 new cases and 250,000 deaths every year. Radiotherapy combined with chemotherapy represents the treatment of choice for advanced cervical carcinomas. The role of the chemotherapy is to increase the sensitivity of the cancer cells to irradiation. Cisplatin, the most commonly used drug for this purpose, has its limitations. Thus, we used a family of ferrocene derivatives (in addition, one new species was prepared using standard Schlenk techniques) and studied their effects on cervical cancer cells alone and in combination with irradiation. We applied colorimetric assay to determine the cytotoxicity of the compounds; flow cytometry to analyze the production of reactive oxygen species (ROS), cell cycle, and mitochondrial membrane potential (MMP); immunochemistry to study protein expression; and colony forming assay to evaluate changes in radiosensitivity. Treatment with ferrocenes exhibited significant cytotoxicity against cervical cancer cells, associated with increasing ROS production and MMP changes, suggesting the induction of apoptosis. The combined activity of ferrocenes and ionizing radiation highlighted ferrocenes as potential radiosensitizing drugs, while their higher single-agent toxicity in comparison with routinely used cisplatin could also be promising. Our results demonstrate antitumor activity of several tested ferrocenes both alone and in combination with radiotherapy.

Special Issue on “Anticancer Drugs Activity and Underlying Mechanisms”

“…In this context, two research studies and one review paper published in this Special Issue are representative of this idea. The first, by Skoupilova et al [15] reported a series of ferrocene derivatives from the general formula [Fe(η 5 -C 5 H 4 CH 2 (p-C 6 H 4 )CH 2 (N-het)) 2 ], which bear either substituted or unsubstituted saturated five-and six-membered nitrogencontaining heterocycles that are able to inhibit the cervical cancer cell growth, with or without the contemporaneous exposure to ionizing radiation. The authors demonstrated that these complexes possessed higher anticancer activity than Cisplatin, which was used as reference, and that the exposure to an ionizing radiation increased the anticancer properties, probably because of a radiosensitizing phenomenon that should be further investigated.…”

Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers

“…The mechanism of their action relies either on the interaction with genomic DNA or the modulation of DNA metabolism. An alternative approach is based on the IR potentiation by drugs increasing intracellular levels of reactive oxygen species (ROS), e.g., sorafenib [ 9 ], l -S-buthionine (BSO) [ 10 ], As 2 O 3 [ 11 ], diisopropylamine dichloroacetate (DADA) [ 12 ] and ferrocene derivatives [ 13 , 14 ]. However, despite their high antitumor efficacy, these drugs also affect healthy tissues and cells, which so far precludes potential clinical applications of RT approaches based on ROS-regulation.…”