Abstract
BACKGROUND/AIMS: Melatonin, synthesized by the pineal gland and released into the blood, appears to have antitumour properties; however, the mechanisms of its anti-cancer effects are largely unknown, especially in stomach cancer. Here, we explore the antitumour activity of melatonin in a gastric cancer cell line (AGS) and analyse its molecular mechanisms.
METHODS: AGS cells were treated with melatonin, and cell viability was assessed using a CCK-8 assay. Flow cytometry was performed to evaluate apoptosis, and protein expression was examined by Western blotting.
RESULTS: Melatonin significantly inhibited cell viability, clone formation, and cell migration and invasion and induced apoptosis in AGS cells. Moreover, MAPK pathways (p38, JNK and ERK) were activated by melatonin treatment, which also significantly increased caspase-3 cleavage and Bax protein expression and decreased Bcl-2 protein expression in a time-dependent manner. Our results demonstrate that p38 and JNK inhibitors (SB203580 and SP600125, respectively) prevented melatonin-induced apoptosis; thus, the propensity of p38 MAPK and JNK to promote apoptosis could be at least partly due to the inhibition of NF-x03BA;B p65 activation by p38 and JNK. Finally, melatonin was able to strengthen cisplatin-mediated antitumour effects in human gastric carcinoma cells by up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and activating the caspase-dependent apoptotic pathway.
CONCLUSION: Melatonin induced apoptosis in AGS cells by activating the caspase-dependent apoptotic pathway and by inhibiting the nuclear translocation of NF-x03BA;B p65, two processes that are regulated by p38 and JNK. Furthermore, melatonin significantly enhanced the anti-tumour effects of cisplatin, with low systemic toxicity. These new findings suggest that melatonin may act as a potent anti-tumour agent and may have great potential as an adjuvant therapy in the future.
See also:
- Official Web Site: The Di Bella Method;
- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;
- About Melatonin - In vitro, review and in vivo publications;
- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);
- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);
- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);
- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;
- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);
- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);
- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);
- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);
- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);
- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);
- Prolactin inhibitors in oncology - In vitro, review and in vivo publications;
- Oesophageal squamocellular carcinoma: a complete and objective response;
- Pancreatic Adenocarcinoma: clinical records on 17 patients treated with Di Bella's Method;
- Complete objective response to biological therapy of plurifocal breast carcinoma;
- Pleural Mesothelioma: clinical records on 11 patients treated with Di Bella's Method;
- Malignant pleural mesothelioma, stage T3-T4. Consideration of a case study;
- Neuroblastoma: Complete objective response to biological treatment;
- Large B-cells Non-Hodgkin's Lymphoma, Stage IV-AE: a Case Report;