Neuropeptide Y receptors 1 and 2 as molecular targets in prostate and breast cancer therapy

Recent advances have revealed the overexpression of Neuropeptide Y (NPY) receptors in multiple cancers, positioning them as attractive molecular targets for cancer diagnostics and therapeutics. Despite this, a comprehensive roadmap for the rational development of anticancer agents targeting NPY receptors remains lacking. Therefore, we present the characteristics of NPY receptor subtypes, their abundance, and the correlation of their expression in different cancer types. It was found that NPY receptor subtypes 1 and 2 were extensively studied, especially in connection with breast and prostate cancer. Many tumors express NPYR, but only breast cancer tissue shows a significant difference in NPYR subtype expression levels between tumor and normal tissues, and, therefore, can represent a promising target. In the context of anticancer therapy, this review provides key findings from the use of wild-type and synthetic NPY analogs. We highlight the critical residues in the NPY sequence that play a critical role in interactions with receptors and provide the recent literature findings on NPY analogues as efficient and specific cancer-targeting agents. Potential solutions to improve NPY analogs' stability are provided, such as sequence modifications of linear peptides, peptide stapling, and conjugation for drug delivery systems. In general, NPY treatment can not be used efficiently as a single therapy but as a combinatorial therapy with anticancer drugs to improve the specificity of the treatment via high-affinity binding to the cancer cells and sensitizing them to chemotherapy. • NPY receptors are overexpressed in cancers, making them attractive diagnostic targets. • Systematic analysis of the expression patterns of NPY receptors in different cancers. • Elucidating the importance of NPY structure for selective binding to receptors. • Review of synthetic NPY analogs with high receptor subtype specificity and affinity. • Discussion on innovative combinations of NPY with other treatments.