Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress Martínez Ruiz, Laura Florido Ruiz, Javier Rodríguez Santana, César López Rodríguez, Alba Guerra Librero Rite, Ana Sánchez Porras, David Fernández Martínez, José González García, Pilar Rusanova Rusanova, Iryna Acuña Castroviejo, Darío Carriel Araya, Víctor Melatonin Intratumoral injection Patient-derived xenograft Head and neck cancer Mitochondria Reactive oxygen species Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patientderived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal- 27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment. 2023-10-30T10:52:02Z 2023-10-30T10:52:02Z 2023-09-15 info:eu-repo/semantics/article L. Martinez-Ruiz et al. Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress. Biomedicine & Pharmacotherapy 167 (2023) 115518[https://doi.org/10.1016/j.biopha.2023.115518] https://hdl.handle.net/10481/85329 10.1016/j.biopha.2023.115518 eng info:eu-repo/grantAgreement/NextGenerationEU/SAF2017-85903‐P; PID2020-115112RB‐I00 http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier