Martino Forino

Breast cancer (BC) is the most frequently diagnosed malignancy and generally the leading cause of cancer-related mortality among women worldwide. Molecular targeted therapies, including endocrine treatment for hormone-responsive tumors, anti-HER2 agents for HER2-positive tumors and PARP inhibitors (PARPis) for homologous recombination-deficient (HRD) tumors, have significantly improved patient outcomes, but several clinical challenges are still open. The development of acquired resistance strongly limits the long-term efficacy of current treatment strategies, underscoring the necessity to identify novel therapeutic approaches for breast cancer therapy. In this review, we summarize and discuss recently investigated natural compounds with anti-breast cancer activity, ranging from polyphenols, terpenoids, alkaloids, sulfur-containing compounds and the emerging plant-derived extracellular vesicles. We focus on their ability to induce DNA damage or oxidative stress, modulating the DNA damage response (DDR) and interfering with key oncogenic signaling pathways. We also discuss the potential of these compounds to enhance the efficacy of conventional therapies, thereby offering a promising role in overcoming clinical resistance. Despite clinical relevance remains under development and further studies are required; many of the natural compounds examined here appear to effectively target DDR signaling and oncogenic pathways, supporting their potential use in breast cancer therapy.

(1) Background: The use of cancer therapy is one of the most challenging arguments in cancer research and is in constant development. One of the principal problems connected with tumor therapy arises from the potential side effects connected with the classical chemotherapeutic treatment but also with molecular target therapy. The identification of novel molecules useful for the reduction of potential side effects but also as a new therapeutic opportunity is one of the hottest topics. (2) Methods: We identified castalin from chestnut shells by using NRM and LC-MS/MS. We treated different cancer cell lines with castalin alone or in combination with a CHK1 inhibitor. Finally, we performed an RNA-seq analysis of HeLa cells treated with castalin. (3) Results: We demonstrated the ability of castalin to induce DNA damage, probably by increasing ROS production. Consistently, antioxidant treatment, with ascorbic acid, reduced the DNA damage induced by castalin. Finally, we demonstrated the potential synergistic effect of castalin with SRA737, a CHK1 inhibitor currently used in clinical trials. (4) Conclusions: We demonstrated the ability of castalin to induce DNA damage favoring NHEJ repair. Moreover, the use of castalin in combination with SRA737 increased the efficacy of the CHK1 inhibitor, reducing its possible side effects.

Grape pomace is the most abundant winery solid waste, accounting for about 60%. Still, it is an unvaluable source of bioactive molecules that can be recovered and reused in the frame of circular economy. In this study Deep Eutectic Solvents (DES) obtained with choline chloride and organic acids by far outperformed conventional solvents (methanol and acetone). In particular, choline chloride:oxalic acid (1:1 at 40°C) emerged as the best one affording a total phenolic content of 43.0 mg/g (dry weight). By means of LC-MS/MS analysis, specific phenols were identified and quantified including anthocyanins, flavan-3-ols, flavonols, phenolic acids and stilbenes. DES extracts also exhibited superior DPPH-based antioxidant activity than conventional ones. These results demonstrated the efficacy of DES in recovering phenolics. The adoption of green solvents for treating waste biomass can significantly benefit wineries and other food industries by increasing their sustainability and diversifying their profits in the frame of circular economy.

The polyphenol extraction and evolution during a traditional 14-day fermentation of the Aglianico red grape, a variety widely cultivated across Southern Italy, was for the first time investigated, with the purpose of optimizing the phenolic profile in finished wines. Anthocyanins, BSA-reactive tannins, iron-reactive phenols, and vanillin-reactive flavans (VRFs) were analyzed in the free-run must, pressed pomace liquid, and in pomace extracts at different maceration times. Experimental evidence suggested that, instead of the typical 14-day maceration of Aglianico grapes, it is recommendable to choose an 11-day maceration in order to prevent the over-extraction of polyphenols that may detrimentally affect the sensory characteristics of wines. In fact, Aglianico wines, if not properly produced, can be affected by excessive astringency due to its high tannin contents. The findings of the present study can provide insightful knowledge to all the winemakers dealing with grape varieties characterized by high quantities of tannins. Also, an earlier racking would supply grape pomaces extremely rich in valuable phenolic compounds to be extracted and reused in several industrial segments in the frame of circular bioeconomy.

Targeting DNA damage response (DDR) pathways represents one of the principal approaches in cancer therapy. However, defects in DDR mechanisms, exhibited by various tumors, can also promote tumor progression and resistance to therapy, negatively impacting patient survival. Therefore, identifying new molecules from natural extracts could provide a powerful source of novel compounds for cancer treatment strategies. In this context, we investigated the role of oleanolic acid (OA), identified in fermented Aglianico red grape pomace, in modulating the DDR in response to camptothecin (CPT), an inhibitor of topoisomerase I. Specifically, we found that OA can influence the choice of DNA repair pathway upon CPT treatment, shifting the repair process from homologous recombination gene conversion to single-strand annealing. Moreover, our data demonstrate that combining sub-lethal concentrations of OA with CPT enhances the efficacy of topoisomerase I inhibition compared to CPT alone. Overall, these findings highlight a new role for OA in the DDR, leading to a more mutagenic DNA repair pathway and increased sensitivity in the HeLa cancer cell line.

Copper (II), a vital fungicide in organic viticulture, also acts as a wine oxidation catalyst. However, limited data are currently available on the impact that maximum allowed copper (II) ion doses in wine grapes at harvest can have on aged wine quality. This was the focus of the present study. We investigated the copper (II) effects by producing both white and red wines from musts containing three initial metal concentrations according to the limits set for organic farming. In detail, the influence of copper (II) on fermentation evolution, chromatic characteristics, and phenolic compounds was evaluated. Interestingly, the white wine obtained with the highest permitted copper (II) dose initially exceeded the concentration of 1.0 mg/L at fermentation completion. However, after one year of storage, the copper (II) content fell below 0.2 ± 0.01 mg/L. Conversely, red wines showed copper (II) levels below 1.0 mg/L at the end of fermentation, but the initial copper (II) level in musts significantly affected total native anthocyanins, color intensity, hue, and acetaldehyde concentration. After 12-month aging, significant differences were observed in polymeric pigments, thus suggesting a potential long-term effect of copper (II) on red wine color stability.

Climate change is causing a significant decrease in the total acidity of grapes and related wines. This represents a serious issue for sparkling wine production. Consequently, before the second fermentation, the acidification of base wines is often necessary. However, the impacts of the most important organic acids on the foam properties of sparkling wines are not yet well known. The impacts of the addition of tartaric, malic, citric, and lactic acid on the quality of Falanghina and Bombino sparkling wines were evaluated. Analyses were performed soon after the second fermentation and one year after aging sur lees. The addition of each different organic acid to the two base wines resulted in significant changes in the sparkling wines not only in terms of pH, titratable acidity, and buffering capacity but also in the content of total amino acids and, in some cases, in the height of the foam and its stability over time. For both grape varieties, acidified wines showed a lower content of total amino acids in comparison with the control wines. The addition of lactic acid determined a higher persistency of the foam even after one year of aging sur lees only in Falanghina wines. The results obtained herein highlight the importance of organic acids and the pH of the base wines for the content of amino acids in sparkling wines. No strict correlation between organic acid addition and the foamability of wines was observed.

Le vinacce, uno dei principali e più ingombranti scarti della filiera vitivinicola, da tempo costituiscono per le aziende un fastidioso fardello di cui disfarsi, con grave dispendio economico e impattanti ripercussioni ambientali. La ricerca scientifica ha tentato negli anni di indicare una strada per mitigare i deleteri effetti dell’accumulo delle vinacce, proponendone un possibile riciclo nell’ottica dell’economia circolare.