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Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity and mortality worldwide, mostly as the population ages. Despite the encouraging advances made over the years in chemotherapy, the development of new compounds for cancer treatments is an urgent priority. In recent years, the design and chemical synthesis of several innovative hybrid molecules, which bring different pharmacophores on the same scaffold, have attracted the interest of many researchers. Following this strategy, we designed and synthetized a series of new hybrid compounds that contain three pharmacophores, namely trimethoxybenzene, thiazolidinedione and thiazole, and tested their anticancer properties on two breast cancer (MCF-7 and MDA-MB-231) cell lines and one melanoma (A2058) cell line. The most active compounds were particularly effective against the MCF-7 cells and did not affect the viability of the normal MCF-10A cells. Docking simulations indicated the human Topoisomerases I and II (hTopos I and II) as possible targets of these compounds, the inhibitory activity of which was demonstrated by the mean of direct enzymatic assays. Particularly, compound 7e was proved to inhibit both the hTopo I and II, whereas compounds 7c,d blocked only the hTopo II. Finally, compound 7e was responsible for MCF-7 cell death by apoptosis. The reported results are promising for the further design and synthesis of other analogues potentially active as anticancer tools.

To date, the 5-year overall survival rate of 60% for early-stage non-small cell lung cancer (NSCLC) is still unsatisfactory. Therefore, reliable prognostic factors are needed. Growing evidence shows that cancer progression may depend on an interconnection between cancer cells and the surrounding tumor microenvironment; hence, circulating molecules may represent promising markers of cancer recurrence. In order to identify a prognostic score, we performed in-depth high-throughput analyses of plasma circulating markers, including exosomal microRNAs (Exo-miR) and peptides, in 67 radically resected NSCLCs. The miRnome profile selected the Exo-miR-130a-3p as the most overexpressed in relapsed patients. Peptidome analysis identified four progressively more degraded forms of fibrinopeptide A (FpA), which were depleted in progressing patients. Notably, stepwise Cox regression analysis selected Exo-miR-130a-3p and the greatest FpA (2-16) to build a score predictive of recurrence, where high-risk patients had 18 months of median disease-free survival. Moreover, in vitro transfections showed that higher levels of miR-130a-3p lead to a deregulation of pathways involved in metastasis and angiogenesis, including the coagulation process and metalloprotease increase which might be linked to FpA reduction. In conclusion, by integrating circulating markers, the identified risk score may help clinicians predict early-stage NSCLC patients who are more likely to relapse after primary surgery.

Chemotherapy is commonly used for cancer treatment, however the lack of selectivity on healthy cells and the development of resistance phenomena are the major issues. A better understanding of cancer genetics helped the development of new targeted anticancer treatments, which permit drug delivery with high specificity and lower toxicity. Moreover, the multi-target drug design concept represents the current trend for future drug research and development. Starting from good results previously obtained by our research group on the resveratrol (RSV) phenylacetamide derivative 2, which displayed an interesting anti-inflammatory and anti-proliferative activity towards the breast cancer cells MCF-7 and MDA-MB-231, we identified other features, as the ability to perturb the cytoskeleton dynamics and interfere with the migration and metastatic processes. In vitro and in silico studies demonstrate that the derivative 2 is a tubulin and actin polymerization inhibitor and an actin depolymerization promotor. In addition, it interferes with the metastatic potential in both the breast cancer cells, inhibiting the in vitro cell migration and decreasing the spheroids number. These promising results demonstrate that the RSV phenylacetamide derivative 2 could be an important starting point in the discovery and development of safer and more efficacy multi-targeted agents.

Transition metal complexes are attracting attention because of their various chemical and biological properties. In particular, the NHC-gold complexes represent a productive field of research in medicinal chemistry, mostly as anticancer tools, displaying a broad range of targets. In addition to the already known biological targets, recently, an important activity in the organization of the cell cytoskeleton was discovered. In this paper, we demonstrated that two NHC-gold complexes (namely AuL4 and AuL7) possessing good anticancer activity and multi-target properties, as stated in our previous studies, play a major role in regulating the actin polymerization, by the means of in silico and in vitro assays. Using immunofluorescence and direct enzymatic assays, we proved that both the complexes inhibited the actin polymerization reaction without promoting the depolymerization of actin filaments. Our outcomes may contribute toward deepening the knowledge of NHC-gold complexes, with the objective of producing more effective and safer drugs for treating cancer diseases.