N-Heterocyclic Carbene Iron Complexes as Anticancer Agents: In Vitro and In Vivo Biological Studies

Abstract

Cisplatin and its derivatives are commonly used in chemotherapeutic treatments of cancer, even though they suffer from many toxic side effects. The problems that emerge from the use of these metal compounds led to the search for new complexes capable to overcome the toxic side effects. Here, we report the evaluation of the antiproliferative activity of Fe(II) cyclopentadienyl complexes bearing n-heterocyclic carbene ligands in tumour cells and their in vivo toxicological profile. The in vitro antiproliferative assays demonstrated that complex Fe1 displays the highest cytotoxic activity both in human colorectal carcinoma cells (HCT116) and ovarian carcinoma cells (A2780) with IC50 values in the low micromolar range. The antiproliferative effect of Fe1 was even higher than cisplatin. Interestingly, Fe1 showed low in vivo toxicity, and in vivo analyses of Fe1 and Fe2 compounds using colorectal HCT116 zebrafish xenograft showed that both reduce the proliferation of human HCT116 colorectal cancer cells in vivo.

Zebrafish xenograft as a tool for the study of colorectal cancer: a review

“…An alternative to this transgenic line is the Tg( kdrl :eGFP) transgenic line that, instead of fli1, uses the promoter for the vascular endothelial growth factor receptor 2 gene (VEGFR2, also known as KDR) [ 63 ]. The two lines provide very similar outcomes when it comes to blood vessel visualization, but while several researchers have chosen the Tg(f li1 :eGFP) line for their study of CRC in zebrafish [ 52 , 59 , 60 , 63 – 70 ] only one group has chosen the Tg( kdrl :eGFP) instead [ 71 ].…”

“…Exceptions to these two methods are the works of Maradonna and colleagues and Roel and colleagues, which use a confocal microscope and calculate the tumor size as the simple sum of the integrated density of the fluorescent intensity of each Z stack [ 59 , 73 ].…”

“…5B ). In the case of injection in the hindbrain ventricle, yolk sack, or PVS, the most frequently used measure of the metastatic potential seems to be the percentage of larvae exhibiting tumor cells outside of the injection site [ 5 , 55 , 59 , 64 , 69 , 75 , 76 ]. An individual with metastasis is often described as having at least one [ 61 ] or three [ 55 , 75 ] tumor cells outside of the injection site.…”

“…An individual with metastasis is often described as having at least one [ 61 ] or three [ 55 , 75 ] tumor cells outside of the injection site. In the case of injection again in the yolk sack or PVS, or the Duct of Cuvier, another prevalent method to determine the metastatic potential is the analysis of the fluorescence intensity of the disseminating cells, either only focused in the tail region [ 5 , 58 , 60 ] or in the whole animal [ 59 , 70 ] (Fig. B2).…”

“…5C ), as well as the rough percentage of embryos/larvae that express a clear angiogenic phenotype as the percentage of embryos presenting ectopic vessels [ 64 , 67 ]. Analysis of the total vessel density (TVD) by using the maximum z-projection and the formula “TVS = GFP area/tumor area” [ 52 , 59 , 74 ] and analysis of the vessel infiltration (VI) by using the maximum z-projection and the formula “VI = GFP area/central tumor area” [ 52 , 74 ]. …”