In Vitro and In Vivo Biological Activities of Dipicolinate Oxovanadium(IV) Complexes

Abstract

The work is focused on anticancer properties of dipicolinate (dipic)-based vanadium(IV) complexes [VO(dipic)(N∩N)] bearing different diimines (2-(1H-imidazol-2-yl)pyridine, 2-(2-pyridyl)benzimidazole, 1,10-phenanthroline-5,6-dione, 1,10-phenanthroline, and 2,2′-bipyridine), as well as differently 4,7-substituted 1,10-phenanthrolines. The antiproliferative effect of V(IV) systems was analyzed in different tumors (A2780, HCT116, and HCT116-DoxR) and normal (primary human dermal fibroblasts) cell lines, revealing a high cytotoxic effect of [VO(dipic)(N∩N)] with 4,7-dimethoxy-phen (5), 4,7-diphenyl-phen (6), and 1,10-phenanthroline (8) against HCT116-DoxR cells. The cytotoxicity differences between these complexes can be correlated with their different internalization by HCT116-DoxR cells. Worthy of note, these three complexes were found to (i) induce cell death through apoptosis and autophagy pathways, namely, through ROS production; (ii) not to be cytostatic; (iii) to interact with the BSA protein; (iv) do not promote tumor cell migration or a pro-angiogenic capability; (v) show a slight in vivo anti-angiogenic capability, and (vi) do not show in vivo toxicity in a chicken embryo.

Copper(II) Complexes with 2,2′:6′,2″-Terpyridine Derivatives Displaying Dimeric Dichloro−μ–Bridged Crystal Structure: Biological Activities from 2D and 3D Tumor Spheroids to In Vivo Models

“…Moreover, it is important to note that for complex 3 , the IC 50 in 3D is still in the low micromolar range (Table ). The results obtained (Table ) are in agreement with other reports, , with a higher concentration of complex being needed in the 3D structure to achieve the same biological effect seen in 2D. The antiproliferative potential values obtained in spheroids are more like those that would be verified in an in vivo model.…”

“…Importantly, this in vivo model is highly relevant as it also allows us to study the in vivo embryotoxicity of our complexes. ,, Indeed, after 48 h of incubation of the complexes with the chicken embryo, no lethality was observed in any of the biological replicates, demonstrating that the complexes do not appear to be toxic (at these IC 50 concentrations) to the chicken embryo.…”

“…In addition, the fluorescence of this complex is detected throughout the cell, including in the nucleus (Figures B, B, S16,S17B). To better clarify these subcellular localizations regarding complexes 2 and 3 and to gather information regarding the internalization and subcellular localization of complexes 5 and 7 in HCT116DoxR cells, ICP-AES was used to quantify the metal (in this case, copper) present in each sample . As copper is an essential metal, the results of the cells exposed to the different complexes were normalized to the values of the cells exposed to the DMSO control.…”

“…Exposure to metal complexes can induce oxidative stress in cells by increasing the number of ROS, leading to disruption of normal cell function and activation of programmed cell death pathways such as apoptosis and autophagy. ,,, …”

“…Since one of the main objectives of researching new complexes is to reduce their side effects on normal tissues, it is essential that these Cu(II) complexes present significantly higher IC 50 values in healthy human cell lines compared to tumor cell lines. Therefore, their relative IC 50 values were also determined in fibroblasts due to their importance in the tumor microenvironment 48 ( Table 1 ).…”