## 4 Promising Neuropeptides Inhibitors for the Development of Effective Cancer Therapy
### Emerging Neuropeptides Inhibitors in Colorectal Cancer
#### 4.1.2 Neurotensin  
Neurotensin (NTS), together with its receptor, plays a pivotal role in stimulating oncogenesis and tumorigenesis in CRC cells and significantly influences many signaling pathways, such as Wnt/\(\beta\)-catenin, MAPK, PI3K/AKT, and Src/Raf dependent pathway. Growing evidence indicates that the NTSR1-NTS interaction activates RAS and PLC, further stimulating other downstream signaling processes. Remarkably, activation of the RAS gene induces an increase in the production of NTS, which exhibits autocrine and paracrine properties and simultaneously upregulates the AKT gene, which has been found to inhibit apoptosis in colon cells [85; 86; 87]. On the other hand, PLC plays a critical role in convert ing PIP2 to IP3, which increases calcium ion production. The increased concentration of calcium ions stimulates several downstream regulatory genes, such as AKT, c-Fos, EGFR, NF-\(\kappa\)B, and CAMKII, which further promote various cellular metabolic processes, such as apoptosis, signal transduction, activation of MAP Kinase, AKT pathway, ion channels modulation, tumor cell proliferation and survival, cell invasion and metastasis. The regulatory role of NTS in promoting CRC through signaling processes has been depicted in Figure 2.  
Researchers highlighted the elevated expression of more than 40% of NTS receptors in human CRC cell lines and activation of the Wnt/APC signaling pathway, which led to the upregulation of their oncogenic activity. It is clear that the NTS-NTSR1 complex in CRC cell lines (HT29, HCT116, SW620, SW480) raises the possibility that this complex increases the risk of CRC progression [122]. Thus, the expression of NTS/NTSR1 directly influences CRC progression and development and can serve as a potential molecular biomarker in CRC diagnosis and prognosis. Several treatments have already been proposed for targeting the expression of NTS/NTSR in CRC. Sodium butyrate (NaBT) was reported to have a beneficial effect in downregulating the NTS and NTSR activity [123]. NaBT is a histone deacetylase inhibitor that directly hinders the functional activity of NTSR mRNA, protein, and promoter function, thereby suspending the growth and proliferation of CRC cells and increasing their apoptosis. In another study, [PERSON] et al. 1996 identified a potent NTSR antagonist, SR48692, which downregulates the expression of NTS and inhibits tumor growth and development [124]. Concurrent work by [PERSON] et al. also considered a similar approach based on a non-peptide NTSR antagonist, i.e., SR 48692. In vitro experiments revealed that SR48692 markedly reduces colony formation by interacting with the NTSR expressed in colon cancer cells [109]. Further support for this positive result was obtained in vivo. Treatment with SR 48,692 (1.7 umol/kg every 24 h) reduced the tumor formed by xenografted SW480 and HCT116 cells in nude mice, suggesting that SR 48,692 deserves further attention as it could be an antagonist with potential anticancer activity in the treatment of colon cancer. Another therapeutic approach exploited the use of various antioxidants and dietary compounds on the activity and function of NTS in  
Figure 2: Signaling cascade driven by NTS interacting with NTSR1. This complex is involved in the gene regulation of various biological processes via activating the RAS-PI3K-AKT and PLC-IP3-Ca\({}^{2+}\), finally contributing to cancer progression. Abbreviations: NTSR1: neurotensin receptor type 1; PI3K: phosphatidylinositol-3-kinase; PLC: protein lipase C; PIP2: phosphatidylinositol-4,5-bisphosphate; IP3: inositol trisphosphate; ER: endoplasmic reticulum; AKT, protein kinase B; EGFR: epidermal growth factor receptor; NF-kB: nuclear factor of kappa-light-chain-enhancer of activated B-cells; CAMKII: calcium/calmodulin-dependent protein kinase II. CRC. For example, natural products, such as curcumin, effectively inhibited the secretion of NTS-mediated IL-8 protein and downregulated the migration activity of colon cells [125].