# New Achievements for the Treatment of Triple-Negative Breast Cancer
## 3 Novel Approaches to Therapy in TNBC
### Drug repurposing for TNBC  
Drug repurposing or drug repositioning is a strategy that significantly reduces the time and the cost of drug development [81]. Indeed, it is known that the discovery and development of a new drug requires much time and countless investments. In addition, almost 90% of newly discovered drugs are later withdrawn due to side effects, thus drug repurposing accelerates clinical trials in light of their previous safety and toxicological studies [82]. This is particularly relevant for TNBC, which currently has the worst prognosis and for which there are few viable treatment options (Table 1) [83]. Several data demonstrated that \(\beta\)-adrenergic signaling in BC activates genes involved in inflammation, ETM processes and angiogenesis [84]. Literature studies demonstrated the ability of \(\beta\)-adrenergic blocker drugs to interfere with TNBC cell proliferation and migration. [PERSON] et al. (2019) [85] assessed that propranolol and the \(\beta_{2}\)-adrenoceptor antagonist ICI 118,551 caused a significant reduction in MDA-MB-231 cell viability, inducing a G0/G1 and S phase cell cycle arrest and apoptosis. This activity is probably linked to the decrease of the phosphorylation levels of extracellular-signal-regulated kinase (ERK)1/2 and the expression levels of cyclo-oxygenase 2 (COX-2) induced by the \(\beta\)-blockers. [PERSON] et al. (2016) [86] also demonstrated that the selective \(\beta\)1-blocker atenol inhibited in vitro cell proliferation in MDA-MB-435 cells and enhanced the ability of metformin to reduce in vivo angiogenesis and metastasis in TNBC cells. [PERSON] et al. (2018) [87] investigated the effect of  
Figure 2: Novel therapeutic approaches for TNBC treatment. osthole, a coumarin derivative mainly used in osteoporosis, in TNBC treatment in vitro and in a xenograft model. The authors found that osthole reduced the growth of a TNBC cell panel, inducing apoptosis in vitro and in vivo. This activity is due to the capability of osthole to inhibit STAT3 phosphorylation and nuclear translocation. [PERSON] et al. (2019) [88] identified two other oral bisphosphonates useful to treat osteoporosis, irsedronate sodium and zoledronic acid, as STAT3 inhibitors by using in silico studies, and they also proved their toxicity to TNBC cells in vitro. Thalidomide, another repurposed cancer drug, was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic teratogenic effects [89]. However, it has recently been successfully used to treat different diseases, including cancer. [PERSON] et al. (2017) [90] reported that some thalidomide-correlated compounds have shown interesting anticancer activity, higher than thalidomide's, against MDA-MB-231 cancer cell lines. Two of them (compounds **1** and **2**) were able to drastically reduce the migration of BC cells by regulation of the two major proteins involved in epithelial-to-mesenchymal transition (EMT): vimentin and E-cadherin. Finally, recent literature studies indicated good anticancer activity in several cancer types by flubendazole and niclosamide, two widely used anthelmintic agents. In particular, [PERSON] et al. (2018) [91] reported that flubendazole treatment produced a significant induction of apoptosis together with G2/M phase accumulation, caspase-3/-7 activation and dysregulation of STAT3 activation in TNBC cells. Flubendazole also increased the activity of two drugs used for TNBC treatment, fluorouracil and doxorubicin, reducing tumor resistance and side effects. The FDA-approved anthelmintic agent niclosamide was found to inhibit TNBC cell growth in vitro and in vivo, reversing EMT and inhibiting the stem-like phenotype in cancer cells [92]. Moreover, in a recent work, repositioning natural products for BC has been proposed [93]. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Structure** & **Name** & **Original Indication** & **Ref** \\ \hline \( \begin{array}{c}\text{O}\text{H}\\ \text{O}\text{H}\end{array} \) & \(