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.

(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.

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.

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