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
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 bi...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223013161 |
| _version_ | 1797660588844777472 |
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| author | Laura Martinez-Ruiz Javier Florido César Rodriguez-Santana Alba López-Rodríguez Ana Guerra-Librero Beatriz I. Fernández-Gil Patricia García-Tárraga José Manuel Garcia-Verdugo Felix Oppel Holger Sudhoff David Sánchez-Porras Amadeo Ten-Steve José Fernández-Martínez Pilar González-García Iryna Rusanova Darío Acuña-Castroviejo Víctor Carriel Germaine Escames |
| author_facet | Laura Martinez-Ruiz Javier Florido César Rodriguez-Santana Alba López-Rodríguez Ana Guerra-Librero Beatriz I. Fernández-Gil Patricia García-Tárraga José Manuel Garcia-Verdugo Felix Oppel Holger Sudhoff David Sánchez-Porras Amadeo Ten-Steve José Fernández-Martínez Pilar González-García Iryna Rusanova Darío Acuña-Castroviejo Víctor Carriel Germaine Escames |
| author_sort | Laura Martinez-Ruiz |
| collection | DOAJ |
| description | 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 patient-derived 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. |
| first_indexed | 2024-03-11T18:32:05Z |
| format | Article |
| id | doaj.art-88cf62c5f1de4102ac70780b346f856d |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T18:32:05Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-88cf62c5f1de4102ac70780b346f856d2023-10-13T11:02:55ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-11-01167115518Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stressLaura Martinez-Ruiz0Javier Florido1César Rodriguez-Santana2Alba López-Rodríguez3Ana Guerra-Librero4Beatriz I. Fernández-Gil5Patricia García-Tárraga6José Manuel Garcia-Verdugo7Felix Oppel8Holger Sudhoff9David Sánchez-Porras10Amadeo Ten-Steve11José Fernández-Martínez12Pilar González-García13Iryna Rusanova14Darío Acuña-Castroviejo15Víctor Carriel16Germaine Escames17Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, SpainDepartment of Neurologic Surgery, Mayo Clinic, Jacksonville, USACavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, SpainCavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, SpainDepartment of Otolaryngology, Head and Neck Surgery, University Hospital OWL of Bielefeld University, Campus Klinikum Bielefeld Mitte, Teutoburger Str. 50, 33604 Bielefeld, GermanyDepartment of Otolaryngology, Head and Neck Surgery, University Hospital OWL of Bielefeld University, Campus Klinikum Bielefeld Mitte, Teutoburger Str. 50, 33604 Bielefeld, GermanyDepartment of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, SpainBiomedical Imaging Research Group (GIBI230-PREBI), La Fe Health Research Institute and Imaging La Fe node at Distributed Network for Biomedical Imaging, Unique Scientific and Technical Infrastructures, Valencia, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, Spain; Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Granada, SpainInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, SpainDepartment of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain; Corresponding author at: Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Granada, Spain.Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain; Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, Spain; Correspondence to: Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n, 18100 Armilla, Granada, Spain.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 patient-derived 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.http://www.sciencedirect.com/science/article/pii/S0753332223013161MelatoninIntratumoral injectionPatient-derived xenograftHead and neck cancerMitochondriaReactive oxygen species |
| spellingShingle | Laura Martinez-Ruiz Javier Florido César Rodriguez-Santana Alba López-Rodríguez Ana Guerra-Librero Beatriz I. Fernández-Gil Patricia García-Tárraga José Manuel Garcia-Verdugo Felix Oppel Holger Sudhoff David Sánchez-Porras Amadeo Ten-Steve José Fernández-Martínez Pilar González-García Iryna Rusanova Darío Acuña-Castroviejo Víctor Carriel Germaine Escames 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 Melatonin Intratumoral injection Patient-derived xenograft Head and neck cancer Mitochondria Reactive oxygen species |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Melatonin Intratumoral injection Patient-derived xenograft Head and neck cancer Mitochondria Reactive oxygen species |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223013161 |
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