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The aim of the present study was the proposal of a strategy to permit the safe use of the powerful antitumor agent Cisplatin. Considering the possibility of reducing the oxidative stress responsible for the Cisplatin induced nephrotoxicity by using antioxidants, such as flavonoids, we proposed the concomitant therapeutic association of Cisplatin with Quercetin. Considering the poor solubility of Quercetin, nanoemulsions have been proposed to encapsulate and facilitate the use of the drug. Originally, the concomitant encapsulation of Quercetin with Cisplatin has been also assessed. The obtained formulations have been characterized and tested against two human cell models, namely the human breast cancer MDA-MB-231 and the normal HEK-293 renal cells. We demonstrated that the new formulated nanoemulsions have improved the anticancer properties of both the molecules and, most importantly, the synergistic effect of the Cisplatin/Quercetin against the MDA-MB-231. Moreover, the dramatic cytotoxic effects of Cisplatin against the human renal HEK-293 cells have been significantly diminished by the use of nanoemulsions containing both the molecules, whereas the antioxidant properties of encapsulated Quercetin have been improved. Finally, the simple process used to obtain the nanoemulsions and the physico-chemical properties compatible with parenteral administration, the stability and the improved pharmaceutical effects contribute to the high potential of this strategy to be studied in future in vivo studies.

The indole scaffold has been recognized, over the years, as a model for the synthesis of compounds with anticancer activity by dint of its substantiated ability to act via multiple mechanisms, which also involves the inhibition of enzymes engaged in DNA replication. In this regard, a new series of indole and pyranoindole derivatives have been prepared, some of which showed good antitumor activity and proved their inhibitory effects on the tubulin target. The anticancer activity of the newly synthesized compounds has been evaluated on breast cancer cell lines, as MCF-7 and MDA-MB231, cervical cancer cells line HeLa and Ishikawa endometrial cancer cell line. Among the compounds under study, 7 exhibited a good antitumor activity on HeLa cell line (IC50 = 3.6 ± 0.5), leading to cell death by apoptosis due to the inhibition of tubulin polymerization, which demonstrated that the compound can explicate its function in a similar way to Vinblastine, a well-known inhibitor of tubulin polymerization. The data were also confirmed by in silico assays. No cytotoxicity against normal cells has been detected. Furthermore, in order to investigate the antioxidant properties, DPPH and ABTS tests were performed, together with fluorescence assays on 3T3-L1 cells. All our findings taken together led us to consider compound 7 a favourable candidate for the battle against cancer.

The applicative potentiality of the nanotechnologies emerges more and more in all fields of science, technology, and medicine. In this context, magnetic nanoparticles have been recently proposed as promising nanomaterials to eliminate, through minimally invasive treatments, small tumours. This work deals with the design and realization of electrospun hybrid membranes of Polycaprolactone (PCL) incorporating magnetic nanoparticles modified with the acid citric-based ligand. The nature of the ligand allows very effective compatibility between nanoparticles and hosting fibers, as deducible by the nanoparticles distribution along the fibers. Dimension and functionalization of the nanoparticles, together with the optimization of the electrospinning parameters allow obtaining highly homogeneous distribution in the diameter of the nanocharged fibers, which ranges between 500 nm and 3 μm. The anticancer activity of the optimized electrospun hybrid membranes has been analyzed toward two different melanoma cell lines: the low metastatic A375 and the high metastatic A2058, using the MTT assay. The formulated membrane exhibited a dose-dependent reduction toward both melanoma cells viability, without a decrease of activity compared to the unfunctionalized Fe3O4 nanoparticles. Promising results have been obtained also considering the antitumor activity of the hybrid Membranes toward uterine HeLa cells. Magnetic properties and structural and morphological characteristics of the functional membranes highlight very promising applications for tuning/enhancing the nanodelivery of drugs and chemotherapy assisted by electroporation technique.

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4–9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4–9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4–9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4).

Statins are the pharmacological inhibitors of cholesterol biosynthesis, acting on key enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR). They are the most effective class of drugs used to treat cardiovascular disease, the main cause of mortality in westernized countries. Our major goal was to investigate the hypocholesterolaemic effects of the 3-hydroxy-3-methyl-glutaryl flavanones enriched fraction (HMGF), extracted from bergamot fruit, in comparison with one of the most used statins, i.e. simvastatin, in a rat model. HMGF and simvastatin reduced the total cholesterol (TC), triacylglycerols (TG), very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) levels, whereas an increase of the high-density lipoproteins (HDL) content was observed exclusively in the HMGF treated rats. Additionally, an appreciable increase of HMGR, LDL receptor (LDLR) and fatty acid synthase (FASN) was evidenced, at mRNA and protein levels. HMGF did not exhibit genotoxic effects and was cytotoxic only at elevated concentrations. The daily supplementation of HMGF in the diet could be very effective for the treatment of hypercholesterolaemia.

Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many tumors. Fatty acid synthase (FASN) is a key lipogenic enzyme catalyzing the terminal steps in the de novo biogenesis of fatty acids. In cancer cells, FASN may act as a metabolic oncogene, given that it confers growth and survival advantages to these cells, whereas its inhibition effectively and selectively kills tumor cells. Hormones such as estrogens and growth factors contribute to the transcriptional regulation of FASN expression also through the activation of downstream signaling and a cross-talk among diverse transduction pathways. In this study, we demonstrate for the first time that 17β-estradiol (E2) and the selective GPER ligand G-1 regulate FASN expression and activity through the GPER-mediated signaling, which involved the EGF receptor/ERK/c-Fos/AP1 transduction pathway, as ascertained by using specific pharmacological inhibitors, performing gene-silencing experiments and ChIP assays in breast SkBr3, colorectal LoVo, hepatocarcinoma HepG2 cancer cells, and breast cancer-associated fibroblasts. In addition, the proliferative effects induced by E2 and G-1 in these cells involved FASN as the inhibitor of its activity, named cerulenin, abolished the growth response to both ligands. Our data suggest that GPER may be included among the transduction mediators involved by estrogens in regulating FASN expression and activity in cancer cells and cancer-associated fibroblasts that strongly contribute to cancer progression.

The androgen receptor (AR) is a proven clinical target in prostate cancer. Recent research indicates that it is an emerging hormonal target in breast cancer as well, with potential clinical benefit in both estrogen receptor(ER) positive and negative tumors. Compared to the ER, AR contains unique functional domains with relevance to its altered role in human breast cancer. The majority of ER-positive tumors express AR, and a significant percentage of ER-negative tumors might benefit from combined targeting of AR and the ErbB2/HER2 oncogene. Signaling downstream of AR might also affect many clinically important pathways which are also emerging clinical targets in breast cancer. AR expression might also play a role during tumor progression to metastatic disease. The role of AR as a new important biomarker in breast cancer will be reviewed herein.