Bello, Ivana (2025) Natural H2S-releasing compounds for adjuvant therapy in breast cancer treatment. [Tesi di dottorato]

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Abstract

Breast cancer (BC) is the most common cancer among women of all ages, with triple-negative breast cancer (TNBC) being the most aggressive subtype, associated with the highest mortality rate. Currently, there are no effective treatments for TNBC, highlighting the urgent need for novel therapeutic options. Plant-derived compounds, particularly isothiocyanates (ITCs) and polysulfides, have gained significant attention for their chemo preventive and anticancer properties. The Brassicaceae family, rich in these phytochemicals such as sulforaphane and erucin (ERU), has shown promise in cancer prevention and therapy. Vegetables like broccoli, cauliflower, and arugula are known for their anticancer effects, largely attributed to ITCs, which inhibit carcinogen-activating enzymes, induce detoxifying enzymes, and promote apoptosis in cancer cells. In my doctoral research, I investigated the anticancer potential of ERU, the main ITC present in Eruca sativa Mill. (E. sativa), comparing it with glucoraphanin from broccoli and diallyl trisulfide (DATS) from garlic. ERU was found to be the most effective, particularly in MDA-MB-231 cells, a well-established in vitro model of TNBC. ERU significantly reduced cell proliferation in a concentration-dependent manner, while also inducing caspase-3-dependent apoptosis and autophagy, as determined by transcriptomic and Western blot analysis of ULK1, ATG13, BECN1, BNIP3, p62 and LC3II. Additionally, ERU prevented intracellular ROS generation by promoting the expression of key antioxidant genes (such as GCLM, HMOX-1, GCLC and SOD1) throughout the Nrf-2 pathway and inhibited MDA-MB-231 cell migration, invasion, and colony formation. In a syngeneic murine model of TNBC using 4T1 cells, oral administration of ERU (10 mg/kg) significantly reduced tumor volume and weight. Furthermore, ERU inhibited the NF-κB signaling pathway, which is critical in TNBC progression, by preventing the degradation of its inhibitor IκB and downregulating the expression of various inflammatory mediators, including cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNFα), interleukins (IL-23, IL-1β, IL-6), transforming growth factor beta (TGF-β), and interferon-gamma (IFN-γ). ERU also inhibited the expression of key markers related to metastasis and angiogenesis, such as C-X-C/C-X-C motif chemokine receptor 4 and ligand 12 (CXCR4 and CXCL12), matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor α (VEGFα), and its receptor (VEGFR) in 4T1-tumors. During the last part of my PhD, I spent six months at Neilos S.r.l., an Italian nutraceutical company, where I analysed the current market for onco-nutraceuticals and proposed the development of an ERU-based dietary supplement for TNBC prevention. The market analysis identified eight existing formulations aimed at cancer prevention. However, none of these contained E. sativa. extract, which is instead used in supplements for preventing hair loss (alopecia) and treating male erectile dysfunction. These findings highlighted that, since ERU has demonstrated anticancer effects and E. sativa extract is already approved for use in dietary supplements, a supplement containing 200 mg of this extract could represent a novel approach for cancer prevention. In conclusion, my research demonstrated that ERU, through multiple mechanisms both in vitro and in vivo, represents a promising candidate for the prevention and therapy of TNBC.

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