In Vitro and In Vivo Effect of Palladacycles: Targeting A2780 Ovarian Carcinoma Cells and Modulation of Angiogenesis

Abstract

Palladacycles are versatile organometallic compounds that show potential for therapeutic use. Here are described the synthesis and characterization of mono-and dinuclear palladacycles bearing diphosphines. Their biological effect was investigated in A2780, an ovarian-derived cancer line, and in normal dermal fibroblasts. The compounds displayed selective cytotoxicity toward the A2780 cell line. Compound 3 decreased the cell viability through cell cycle retention in G0/G1, triggered apoptosis through the intrinsic pathway, and induced autophagy in A2780 cells. Compound 9 also induced cell cycle retention, apoptosis, and cellular detachment. Notably, compound 9 induced the production of intracellular reactive oxygen species (ROS). Our work demonstrated that compound 3 enters A2780 cells via active transport, which requires energy, while compound 9 enters A2780 cells mostly passively. The potential effect of palladacycles in angiogenesis was investigated for the first time in an in vivo chorioallantoic membrane model, showing that while compound 3 displayed an antiangiogenic effect crucial to fighting cancer progression, compound 9 promoted angiogenesis. These results show that palladacycles may be used in different clinical applications where pro-or antiangiogenic effects may be desirable.

Triazole-Based Half-Sandwich Ruthenium(II) Compounds: From In Vitro Antiproliferative Potential to In Vivo Toxicity Evaluation

“…Some years ago, the chick chorioallantoic membrane (CAM) model was described as an excellent in vivo model to study the effect of newly identified molecules in angiogenesis and tumor invasion of colorectal, prostate, brain cancer, and ovarian cancers . Moreover, in vivo model toxicity effects might also be studied, as recently described by us for palladacycles . This prompted us to also test compounds 1 and 3 in this model in terms of toxicity and antiangiogenic potential using as a model ex ovo CAM …”

Bioactivity and Development of Small Non-Platinum Metal-Based Chemotherapeutics

“…They can be synthesized using bidentate bridging ligands (e.g., bidentate phosphine ligands), together with additional ligands selected for their capability to trigger interactions with a biomolecular target [ 192 , 193 ]. Several of these derivatives showed higher anticancer activity than the mononuclear complexes when tested in vitro and in vivo against different human tumours associated with several types of mechanisms of action, including DNA damage, inhibition of cancer cell metabolism, mitochondrial dysfunctions, apoptosis, and autophagy, as well as angiogenesis modulation [ 185 , 194 , 195 ]. More recently, a novel binuclear palladacycle derivative referred to as AJ-5 has shown in various experimental models in vitro to be particularly active, with a good safety profile in vivo.…”

Vanadium(IV) Complexes with Methyl-Substituted 8-Hydroxyquinolines: Catalytic Potential in the Oxidation of Hydrocarbons and Alcohols with Peroxides and Biological Activity

“…To evaluate if the observed apoptosis induction in the HCT116 cell line is triggered by the intrinsic pathway, due to destabilization of mitochondria, changes in the mitochondrial membrane potential were evaluated using JC-1 dye (Abnova). This is a green fluorescent dye as a monomer; however, it will aggregate in the presence of a normal mitochondrial potential, which will cause a red-shift in emission spectra [97]. Measuring the green and red fluorescence by flow cytometry it is possible to calculate normalized ratios that can show us if there is an increase or decrease in the mitochondrial membrane potential (Figure 15).…”

“…Cells were also incubated with DMSO 0.1% (vehicle control) and cisplatin 15 µM (positive control). Following the manufacturer's instructions, after this incubation period, cells were detached with trypsin, washed with PBS 1× and incubated 15 min at room temperature with Annexin V-Alexa fluor 488 assay solution and 10 µg mL −1 propidium iodide [97,104]. An Attune acoustic focusing cytometer (ThermoFisher Scientific, Waltham, MA, USA) was used to analyze cells and the resulting information was processed with the respective Attune Cytometric Software 2.1 (ThermoFisher Scientific, Waltham, MA, USA).…”

“…The induction of ROS in HCT116 cells was evaluated indirectly by flow cytometry using a specific dye, 2 ,7 -dichlorodihydrofluorescein diacetate (H 2 DCF-DA) (Thermo Fischer Scientific). In the presence of ROS, intracellular esterases remove the acetate groups of the dye which leads to an increased fluorescence [97,104]. HCT116 cells were seeded in 6-well plates (4 × 10 5 cells per well) for the initial 24 h of incubation.…”