Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy

Beatriz I. Fernandez-Gil, Ana Guerra-Librero, Ying Qiang Shen, Javier Florido, Laura Martínez-Ruiz, Sergio García-López, Christian Adan, César Rodríguez-Santana, Darío Acuña-Castroviejo, Alfredo Quinones-Hinojosa, José Fernández-Martínez, Ahmed E. Abdel Moneim, Luis C. López, José M. Rodríguez Ferrer, Germaine Escames

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 μM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.

Original languageEnglish (US)
Article number7187128
JournalOxidative Medicine and Cellular Longevity
Volume2019
DOIs
StatePublished - Jan 1 2019

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Autophagy
Melatonin
Cytotoxicity
Cisplatin
Radiation
Apoptosis
Radiotherapy
Therapeutics
Mitochondria
Oncology
Glutathione Disulfide
Medical Oncology
Flow cytometry
Carcinoma, squamous cell of head and neck
Epithelial Cells
Enzyme activity
Head and Neck Neoplasms
Treatment Failure
Radio
Mitochondrial DNA

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Cell Biology

Cite this

Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy. / Fernandez-Gil, Beatriz I.; Guerra-Librero, Ana; Shen, Ying Qiang; Florido, Javier; Martínez-Ruiz, Laura; García-López, Sergio; Adan, Christian; Rodríguez-Santana, César; Acuña-Castroviejo, Darío; Quinones-Hinojosa, Alfredo; Fernández-Martínez, José; Abdel Moneim, Ahmed E.; López, Luis C.; Rodríguez Ferrer, José M.; Escames, Germaine.

In: Oxidative Medicine and Cellular Longevity, Vol. 2019, 7187128, 01.01.2019.

Research output: Contribution to journalArticle

Fernandez-Gil, BI, Guerra-Librero, A, Shen, YQ, Florido, J, Martínez-Ruiz, L, García-López, S, Adan, C, Rodríguez-Santana, C, Acuña-Castroviejo, D, Quinones-Hinojosa, A, Fernández-Martínez, J, Abdel Moneim, AE, López, LC, Rodríguez Ferrer, JM & Escames, G 2019, 'Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy', Oxidative Medicine and Cellular Longevity, vol. 2019, 7187128. https://doi.org/10.1155/2019/7187128
Fernandez-Gil, Beatriz I. ; Guerra-Librero, Ana ; Shen, Ying Qiang ; Florido, Javier ; Martínez-Ruiz, Laura ; García-López, Sergio ; Adan, Christian ; Rodríguez-Santana, César ; Acuña-Castroviejo, Darío ; Quinones-Hinojosa, Alfredo ; Fernández-Martínez, José ; Abdel Moneim, Ahmed E. ; López, Luis C. ; Rodríguez Ferrer, José M. ; Escames, Germaine. / Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy. In: Oxidative Medicine and Cellular Longevity. 2019 ; Vol. 2019.
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