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.
Highlights
IntroductionHead and neck cancer, which is the sixth leading cancer by incidence worldwide, with more than 300,000 mortalities annually [1], has become a major health burden, especially as cell resistance to radio and chemotherapy develops
Head and neck cancer, which is the sixth leading cancer by incidence worldwide, with more than 300,000 mortalities annually [1], has become a major health burden, especially as cell resistance to radio and chemotherapy develops.Radiotherapy (RT), which is one of the most commonly used tumor treatments [2], damages biomolecules, such as Oxidative Medicine and Cellular Longevity proteins and lipoids, DNA, resulting in the termination of cell division and proliferation and even in cell necrosis or apoptosis
The cells were cultured in high-glucose Dulbecco’s modified Eagle’s medium (DMEM), GlutaMAX supplemented with 10% fetal bovine serum, and 2% antibiotic-antimycotic (Fisher Scientific, Madrid, Spain) for Cal-27 and were grown in DMEM-F12 Nutrient Mixture Ham medium (1 : 1) containing 2 mM L-glutamine (Fisher Scientific, Madrid, Spain) and 0.5 mM sodium pyruvate supplemented with 10% FBS, 0.4 μg/mL hydrocortisone (Sigma-Aldrich, Madrid, Spain), and 2% antibiotic-antimycotic for SCC-9
Summary
Head and neck cancer, which is the sixth leading cancer by incidence worldwide, with more than 300,000 mortalities annually [1], has become a major health burden, especially as cell resistance to radio and chemotherapy develops. Radiotherapy (RT), which is one of the most commonly used tumor treatments [2], damages biomolecules, such as Oxidative Medicine and Cellular Longevity proteins and lipoids, DNA, resulting in the termination of cell division and proliferation and even in cell necrosis or apoptosis. CDDP induces mitochondria-dependent reactive oxygen species (ROS) formation which contributes to cell-killing processes by enhancing the damaging effect of drugs on nuclear DNA (nDNA) [4]. The high incidence of chemoresistance and its many side effects limit the clinical usefulness of CDDP as an anticancer treatment [5, 6]. New anticancer therapeutic strategies to attenuate cytotoxicity in normal tissues and to prevent or reverse the development of radio and chemoresistance are required
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