# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 4 Therapeutic Strategies and Future Directions  
Despite all the progress that has been made in the fight against cancer, this disease continues to be a major health problem. According to data provided by the GLOBOCAN database ([[https://gco.iarc.fr/](https://gco.iarc.fr/)]([https://gco.iarc.fr/](https://gco.iarc.fr/)) accessed on 27 May 2023) [129], it is estimated that in 2020 there were more than 19 million new cases of cancer, of which almost 50% were found in Asia and almost 23% in Europe. A lesser percentage was detected in North America (13.3%), Latin America, the Caribbean (7.6%), Africa (5.7%), and Oceania (1.3%). Concerning incidence and mortality rates, the highest incidence rate corresponded to breast cancer (47.8%), with a mortality rate of 13.6%. The highest mortality rate was detected in lung cancer (18%), although its incidence was 22.4%, much lower than breast cancer. These data  
\begin{table}
\begin{tabular}{c c c} \hline
**Tumor** & **Orexigenic System** & **References** \\ \hline \hline \multicolumn{3}{c}{OXRs expression: more widespread in prostate cancer than in benign prostate} \\ \multicolumn{3}{c}{hyperplasia or chronic prostatitis.} \\ \multicolumn{3}{c}{OXR expression indicator of poor prognosis.} \\ \multicolumn{3}{c}{OXR1 promoted apoptosis and overexpressed in advanced tumors, but its} \\ \multicolumn{3}{c}{expression was lower in low-grade tumors.} \\ \multicolumn{3}{c}{Orexin A/OXR2 involved in maintenance and/or pathogenesis of benign prostatic hyperplasia.} \\ \multicolumn{3}{c}{Prostate cancer} & \multicolumn{1}{c}{Orexin A upregulated OXR1 expression and decreased LNCaP cell survival.} \\ \multicolumn{3}{c}{Orexin A, via OXR1, interfered with androgen receptor activity, which controls} \\ \multicolumn{3}{c}{cancer onset and progression.} \\ \multicolumn{3}{c}{Orexins increased non-transformed DU14 Scell growth, but, after neuroendocrine transformation, apoptosis was observed after treatment with orexin A.} \\ \multicolumn{3}{c}{Orexin A, via OXR1, blocked cell growth in LNCaP and Du145 cells, and the peptide} \\ \multicolumn{3}{c}{ decreased the tumor volume of xenografted Du145 cells.} \\ \multicolumn{3}{c}{Orexin A increased OXR1 expression in LNCaP cells.} \\ \hline \hline \end{tabular}
\end{table}
Table 1: \(Cont.\)  
Figure 2: Summary of the actions mediated by the orexinergic system in cancer cells. Depending on the tumors’ onexins, through OXR, they favor (\(\dagger\)) or block (\(\downarrow\)) tumor cell proliferation and apoptosis. OXR agonists (when orexins inhibit cell proliferation and promote apoptosis) or OXR antagonists (when orexins favor cell proliferation and block apoptosis) could be used to counteract tumor progression. Akt: protein kinase B; Bcl-2: B cell lymphoma; HIF-1\(\alpha\): hypoxia-inducible factor; mTOR: mammalian target of rapamycin; OXR1: orexin receptor 1; OXR2: orexin receptor 2. \(\uparrow\): increase; \(\downarrow\): decrease.  
reflect that, although rates are continually improving, there is still much work to be done in terms of early detection and treatment. Knowledge of the orexinergic system may provide an additional resource as a potential therapeutic target in the fight against cancer.